%0 Journal Article %J Virus Evol %D 2024 %T Inter and intra-host diversity of RSV in hematopoietic stem cell transplant adults with normal and delayed viral clearance. %A Avadhanula, Vasanthi %A Agustinho, Daniel Paiva %A Menon, Vipin Kumar %A Chemaly, Roy F %A Shah, Dimpy P %A Xiang Qin %A Surathu, Anil %A Harshavardhan Doddapaneni %A Donna M Muzny %A Ginger A Metcalf %A Cregeen, Sara Javornik %A Richard A Gibbs %A Petrosino, Joseph F %A Fritz J Sedlazeck %A Piedra, Pedro A %X

Respiratory syncytial virus (RSV) infection in immunocompromised individuals often leads to prolonged illness, progression to severe lower respiratory tract infection, and even death. How the host immune environment of the hematopoietic stem cell transplant (HCT) adults can affect viral genetic variation during an acute infection is not understood well. In the present study, we performed whole genome sequencing of RSV/A or RSV/B from samples collected longitudinally from HCT adults with normal (<14 days) and delayed (≥14 days) RSV clearance who were enrolled in a ribavirin trial. We determined the inter-host and intra-host genetic variation of RSV and the effect of mutations on putative glycosylation sites. The inter-host variation of RSV is centered in the attachment (G) and fusion (F) glycoprotein genes followed by polymerase (L) and matrix (M) genes. Interestingly, the overall genetic variation was constant between normal and delayed clearance groups for both RSV/A and RSV/B. Intra-host variation primarily occurred in the G gene followed by non-structural protein (NS1) and L genes; however, gain or loss of stop codons and frameshift mutations appeared only in the G gene and only in the delayed viral clearance group. Potential gain or loss of O-linked glycosylation sites in the G gene occurred both in RSV/A and RSV/B isolates. For RSV F gene, loss of N-linked glycosylation site occurred in three RSV/B isolates within an antigenic epitope. Both oral and aerosolized ribavirin did not cause any mutations in the L gene. In summary, prolonged viral shedding and immune deficiency resulted in RSV variation, especially in structural mutations in the G gene, possibly associated with immune evasion. Therefore, sequencing and monitoring of RSV isolates from immunocompromised patients are crucial as they can create escape mutants that can impact the effectiveness of upcoming vaccines and treatments.

%B Virus Evol %V 10 %P vead086 %8 2024 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/38361816?dopt=Abstract %R 10.1093/ve/vead086 %0 Journal Article %J bioRxiv %D 2023 %T Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk. %A Behera, S %A Belyeu, J R %A Chen, X %A Paulin, L F %A Nguyen, N Q H %A Newman, E %A Mahmoud, M %A Menon, V K %A Qi, Q %A Joshi, P %A Marcovina, S %A Rossi, M %A Roller, E %A Han, J %A Onuchic, V %A Avery, C L %A Ballantyne, C M %A Rodriguez, C J %A Kaplan, R C %A Donna M Muzny %A Ginger A Metcalf %A Richard A Gibbs %A Yu, B %A Eric Boerwinkle %A Eberle, M A %A Fritz J Sedlazeck %X

The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase ~50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.

%B bioRxiv %8 2023 Apr 27 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/37163057?dopt=Abstract %R 10.1101/2023.04.24.538128 %0 Journal Article %J bioRxiv %D 2023 %T Longitudinal host transcriptional responses to SARS-CoV-2 infection in adults with extremely high viral load. %A Avadhanula, Vasanthi %A Creighton, Chad J %A Ferlic-Stark, Laura %A Sucgang, Richard %A Zhang, Yiqun %A Nagaraj, Divya %A Nicholson, Erin G %A Rajan, Anubama %A Menon, Vipin Kumar %A Harshavardhan Doddapaneni %A Donna M Muzny %A Ginger A Metcalf %A Cregeen, Sara Joan Javornik %A Hoffman, Kristi Louise %A Richard A Gibbs %A Petrosino, Joseph %A Piedra, Pedro A %X

Current understanding of viral dynamics of SARS-CoV-2 and host responses driving the pathogenic mechanisms in COVID-19 is rapidly evolving. Here, we conducted a longitudinal study to investigate gene expression patterns during acute SARS-CoV-2 illness. Cases included SARS-CoV-2 infected individuals with extremely high viral loads early in their illness, individuals having low SARS-CoV-2 viral loads early in their infection, and individuals testing negative for SARS-CoV-2. We could identify widespread transcriptional host responses to SARS-CoV-2 infection that were initially most strongly manifested in patients with extremely high initial viral loads, then attenuating within the patient over time as viral loads decreased. Genes correlated with SARS-CoV-2 viral load over time were similarly differentially expressed across independent datasets of SARS-CoV-2 infected lung and upper airway cells, from both in vitro systems and patient samples. We also generated expression data on the human nose organoid model during SARS-CoV-2 infection. The human nose organoid-generated host transcriptional response captured many aspects of responses observed in the above patient samples, while suggesting the existence of distinct host responses to SARS-CoV-2 depending on the cellular context, involving both epithelial and cellular immune responses. Our findings provide a catalog of SARS-CoV-2 host response genes changing over time.

%B bioRxiv %8 2023 May 25 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/37292999?dopt=Abstract %R 10.1101/2023.05.24.542181 %0 Journal Article %J Circ Genom Precis Med %D 2023 %T Rare Genetic Variants Associated With Sudden Cardiac Arrest in the Young: A Prospective, Population-Based Study. %A Holmstrom, Lauri %A Chaudhary, Ninad S %A Nakamura, Kotoka %A Chugh, Harpriya %A Uy-Evanado, Audrey %A Norby, Faye %A Ginger A Metcalf %A Menon, Vipin K %A Yu, Bing %A Eric Boerwinkle %A Chugh, Sumeet S %A Akdemir, Zeynep %A Kransdorf, Evan P %K Death, Sudden, Cardiac %K Heart Arrest %K Humans %K Prospective Studies %B Circ Genom Precis Med %V 16 %P 404-405 %8 2023 Aug %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/37194601?dopt=Abstract %R 10.1161/CIRCGEN.123.004105 %0 Journal Article %J Circ Genom Precis Med %D 2023 %T Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program. %A Seyerle, Amanda A %A Laurie, Cecelia A %A Coombes, Brandon J %A Jain, Deepti %A Conomos, Matthew P %A Brody, Jennifer %A Chen, Ming-Huei %A Gogarten, Stephanie M %A Beutel, Kathleen M %A Gupta, Namrata %A Heckbert, Susan R %A Jackson, Rebecca D %A Johnson, Andrew D %A Ko, Darae %A Manson, JoAnn E %A McKnight, Barbara %A Ginger A Metcalf %A Morrison, Alanna C %A Reiner, Alexander P %A Sofer, Tamar %A Tang, Weihong %A Wiggins, Kerri L %A Eric Boerwinkle %A de Andrade, Mariza %A Gabriel, Stacey B %A Richard A Gibbs %A Laurie, Cathy C %A Psaty, Bruce M %A Vasan, Ramachandran S %A Rice, Ken %A Kooperberg, Charles %A Pankow, James S %A Smith, Nicholas L %A Pankratz, Nathan %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Precision Medicine %K Venous Thromboembolism %X

BACKGROUND: Risk for venous thromboembolism has a strong genetic component. Whole genome sequencing from the TOPMed program (Trans-Omics for Precision Medicine) allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies.

METHODS: The 3793 cases and 7834 controls (11.6% of cases were individuals of African, Hispanic/Latino, or Asian ancestry) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants).

RESULTS: Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only (odds ratio, 6.2 for carriers of rare variants; =7.4×10) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at (odds ratio, 3.8; =1.6×10), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: became significant (minimum =1.8×10 with the secondary filter), while did not (minimum =4.4×10 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, , became significant (=4.4×10 using all missense variants with minor allele frequency <0.0005).

CONCLUSIONS: Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel locus and to identify additional rare variation associated with venous thromboembolism.

%B Circ Genom Precis Med %V 16 %P e003532 %8 2023 Apr %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/36960714?dopt=Abstract %R 10.1161/CIRCGEN.121.003532 %0 Journal Article %J Hum Mol Genet %D 2023 %T Whole-exome sequencing study identifies four novel gene loci associated with diabetic kidney disease. %A Pan, Yang %A Sun, Xiao %A Mi, Xuenan %A Huang, Zhijie %A Hsu, Yenchih %A Hixson, James E %A Munzy, Donna %A Ginger A Metcalf %A Franceschini, Nora %A Tin, Adrienne %A Köttgen, Anna %A Francis, Michael %A Brody, Jennifer A %A Kestenbaum, Bryan %A Sitlani, Colleen M %A Mychaleckyj, Josyf C %A Kramer, Holly %A Lange, Leslie A %A Guo, Xiuqing %A Hwang, Shih-Jen %A Irvin, Marguerite R %A Smith, Jennifer A %A Yanek, Lisa R %A Vaidya, Dhananjay %A Chen, Yii-Der Ida %A Fornage, Myriam %A Lloyd-Jones, Donald M %A Hou, Lifang %A Mathias, Rasika A %A Mitchell, Braxton D %A Peyser, Patricia A %A Kardia, Sharon L R %A Arnett, Donna K %A Correa, Adolfo %A Raffield, Laura M %A Vasan, Ramachandran S %A Cupple, L Adrienne %A Levy, Daniel %A Kaplan, Robert C %A North, Kari E %A Rotter, Jerome I %A Kooperberg, Charles %A Reiner, Alexander P %A Psaty, Bruce M %A Tracy, Russell P %A Richard A Gibbs %A Morrison, Alanna C %A Feldman, Harold %A Eric Boerwinkle %A He, Jiang %A Kelly, Tanika N %K Aminopeptidases %K Diabetes Mellitus %K Diabetic Nephropathies %K Exome Sequencing %K Humans %K Kidney %K Renal Insufficiency, Chronic %X

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease and diabetes. Our two-stage WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies (stage 1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine participants (stage 2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single-variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds [95% confidence interval (CI): 33.6, 1105] of DKD compared with noncarriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% CI: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

%B Hum Mol Genet %V 32 %P 1048-1060 %8 2023 Mar 06 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/36444934?dopt=Abstract %R 10.1093/hmg/ddac290 %0 Journal Article %J Gigascience %D 2022 %T Fully resolved assembly of Cryptosporidium parvum. %A Vipin Menon %A Okhuysen, Pablo C %A Chappell, Cynthia L %A Mahmoud, Medhat %A Mahmoud, Medhat %A Meng, Qingchang %A Harshavardhan Doddapaneni %A Vee, Vanesa %A Yi Han %A Salvi, Sejal %A Bhamidipati, Sravya %A Kottapalli, Kavya %A Weissenberger, George %A Shen, Hua %A Ross, Matthew C %A Hoffman, Kristi L %A Cregeen, Sara Javornik %A Donna M Muzny %A Ginger A Metcalf %A Richard A Gibbs %A Petrosino, Joseph F %A Fritz J Sedlazeck %K Cryptosporidiosis %K Cryptosporidium %K Cryptosporidium parvum %K Genome %K Genomics %K Humans %X

BACKGROUND: Cryptosporidium parvum is an apicomplexan parasite commonly found across many host species with a global infection prevalence in human populations of 7.6%. Understanding its diversity and genomic makeup can help in fighting established infections and prohibiting further transmission. The basis of every genomic study is a high-quality reference genome that has continuity and completeness, thus enabling comprehensive comparative studies.

FINDINGS: Here, we provide a highly accurate and complete reference genome of Cryptosporidium parvum. The assembly is based on Oxford Nanopore reads and was improved using Illumina reads for error correction. We also outline how to evaluate and choose from different assembly methods based on 2 main approaches that can be applied to other Cryptosporidium species. The assembly encompasses 8 chromosomes and includes 13 telomeres that were resolved. Overall, the assembly shows a high completion rate with 98.4% single-copy BUSCO genes.

CONCLUSIONS: This high-quality reference genome of a zoonotic IIaA17G2R1 C. parvum subtype isolate provides the basis for subsequent comparative genomic studies across the Cryptosporidium clade. This will enable improved understanding of diversity, functional, and association studies.

%B Gigascience %V 11 %8 2022 Feb 15 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/35166336?dopt=Abstract %R 10.1093/gigascience/giac010 %0 Journal Article %J Circ Genom Precis Med %D 2022 %T Patient and Clinician Perceptions of Precision Cardiology Care: Findings From the HeartCare Study. %A Smith, Hadley Stevens %A Sanchez, Clarissa E %A Maag, Ronald %A Buentello, Alexandria %A David R Murdock %A Ginger A Metcalf %A Hadley, Trevor D %A Riconda, Daniel L %A Eric Boerwinkle %A Wehrens, Xander H T %A Ballantyne, Christie M %A Richard A Gibbs %A McGuire, Amy L %A Pereira, Stacey %K Cardiology %K Cardiovascular Diseases %K Clinical Decision-Making %K Family %K Humans %K Surveys and Questionnaires %X

BACKGROUND: Routine genome-wide screening for cardiovascular disease risk may inform clinical decision-making. However, little is known about whether clinicians and patients would find such testing useful or acceptable within the context of a genomics-enabled learning health system.

METHODS: We conducted surveys with patients and their clinicians who were participating in the HeartCare Study, a precision cardiology care project that returned results from a next-generation sequencing panel of 158 genes associated with cardiovascular disease risk. Six weeks after return of results, we assessed patients' and clinicians' perceived utility and disutility of HeartCare, the effect of the test on clinical recommendations, and patients' attitudes toward integration of research and clinical care.

RESULTS: Among 666 HeartCare patients with a result returned during the survey study period, 42.0% completed a full or partial survey. Patient-participants who completed a full survey (n=224) generally had positive perceptions of HeartCare independent of whether they received a positive or negative result. Most patient-participants considered genetic testing for cardiovascular disease risk to have more benefit than risk (88.3%) and agreed that it provided information that they wanted to know (81.2%), while most disagreed that the test caused them to feel confused (77.7%) or overwhelmed (78.0%). For 122 of their patients with positive results, clinicians (n=13) reported making changes in clinical care for 66.4% of patients, recommending changes in health behaviors for 36.9% of patients, and recommending to 33.6% of patients that their family members have clinical testing.

CONCLUSIONS: Both patients and clinicians thought the HeartCare panel screen for cardiovascular disease risk provided information that was useful in terms of personal or health benefits to the patient and that informed clinical care without causing patients to be confused or overwhelmed. Further research is needed to assess perceptions of genome-wide screening among the US cardiology clinic population.

%B Circ Genom Precis Med %V 15 %P e003605 %8 2022 Dec %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/36282588?dopt=Abstract %R 10.1161/CIRCGEN.121.003605 %0 Journal Article %J Am J Hum Genet %D 2022 %T Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program. %A Hu, Xiaowei %A Qiao, Dandi %A Kim, Wonji %A Moll, Matthew %A Balte, Pallavi P %A Lange, Leslie A %A Bartz, Traci M %A Kumar, Rajesh %A Li, Xingnan %A Yu, Bing %A Cade, Brian E %A Laurie, Cecelia A %A Sofer, Tamar %A Ruczinski, Ingo %A Nickerson, Deborah A %A Donna M Muzny %A Ginger A Metcalf %A Harshavardhan Doddapaneni %A Gabriel, Stacy %A Gupta, Namrata %A Dugan-Perez, Shannon %A Cupples, L Adrienne %A Loehr, Laura R %A Jain, Deepti %A Rotter, Jerome I %A Wilson, James G %A Psaty, Bruce M %A Fornage, Myriam %A Morrison, Alanna C %A Vasan, Ramachandran S %A Washko, George %A Rich, Stephen S %A O'Connor, George T %A Bleecker, Eugene %A Kaplan, Robert C %A Kalhan, Ravi %A Redline, Susan %A Gharib, Sina A %A Meyers, Deborah %A Ortega, Victor %A Dupuis, Josée %A London, Stephanie J %A Lappalainen, Tuuli %A Oelsner, Elizabeth C %A Silverman, Edwin K %A Barr, R Graham %A Thornton, Timothy A %A Wheeler, Heather E %A Cho, Michael H %A Im, Hae Kyung %A Manichaikul, Ani %K Humans %K Lung %K National Heart, Lung, and Blood Institute (U.S.) %K Pulmonary Disease, Chronic Obstructive %K Risk Factors %K Transcriptome %K United States %X

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV] and its ratio to forced vital capacity [FEV/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV and FEV/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p < 2.2 × 10 with portability gains ranging from 5% to 28%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.

%B Am J Hum Genet %V 109 %P 857-870 %8 2022 May 05 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/35385699?dopt=Abstract %R 10.1016/j.ajhg.2022.03.007 %0 Journal Article %J Am J Hum Genet %D 2022 %T Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. %A Hindy, George %A Dornbos, Peter %A Chaffin, Mark D %A Liu, Dajiang J %A Wang, Minxian %A Selvaraj, Margaret Sunitha %A Zhang, David %A Park, Joseph %A Aguilar-Salinas, Carlos A %A Antonacci-Fulton, Lucinda %A Ardissino, Diego %A Arnett, Donna K %A Aslibekyan, Stella %A Atzmon, Gil %A Ballantyne, Christie M %A Barajas-Olmos, Francisco %A Barzilai, Nir %A Becker, Lewis C %A Bielak, Lawrence F %A Bis, Joshua C %A Blangero, John %A Eric Boerwinkle %A Bonnycastle, Lori L %A Bottinger, Erwin %A Bowden, Donald W %A Bown, Matthew J %A Brody, Jennifer A %A Broome, Jai G %A Burtt, Noël P %A Cade, Brian E %A Centeno-Cruz, Federico %A Chan, Edmund %A Chang, Yi-Cheng %A Chen, Yii-Der I %A Cheng, Ching-Yu %A Choi, Won Jung %A Chowdhury, Rajiv %A Contreras-Cubas, Cecilia %A Córdova, Emilio J %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A Danesh, John %A de Vries, Paul S %A DeFronzo, Ralph A %A Harshavardhan Doddapaneni %A Duggirala, Ravindranath %A Dutcher, Susan K %A Ellinor, Patrick T %A Emery, Leslie S %A Florez, Jose C %A Fornage, Myriam %A Freedman, Barry I %A Fuster, Valentin %A Garay-Sevilla, Ma Eugenia %A García-Ortiz, Humberto %A Germer, Soren %A Richard A Gibbs %A Gieger, Christian %A Glaser, Benjamin %A Gonzalez, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Graff, Mariaelisa %A Graham, Sarah E %A Grarup, Niels %A Groop, Leif C %A Guo, Xiuqing %A Gupta, Namrata %A Han, Sohee %A Hanis, Craig L %A Hansen, Torben %A He, Jiang %A Heard-Costa, Nancy L %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Irvin, Marguerite R %A Islas-Andrade, Sergio %A Jarvik, Gail P %A Kang, Hyun Min %A Kardia, Sharon L R %A Kelly, Tanika %A Kenny, Eimear E %A Khan, Alyna T %A Kim, Bong-Jo %A Kim, Ryan W %A Kim, Young Jin %A Koistinen, Heikki A %A Kooperberg, Charles %A Kuusisto, Johanna %A Kwak, Soo Heon %A Laakso, Markku %A Lange, Leslie A %A Lee, Jiwon %A Lee, Juyoung %A Lee, Seonwook %A Lehman, Donna M %A Lemaitre, Rozenn N %A Linneberg, Allan %A Liu, Jianjun %A Loos, Ruth J F %A Lubitz, Steven A %A Lyssenko, Valeriya %A Ma, Ronald C W %A Martin, Lisa Warsinger %A Martínez-Hernández, Angélica %A Mathias, Rasika A %A McGarvey, Stephen T %A McPherson, Ruth %A Meigs, James B %A Meitinger, Thomas %A Melander, Olle %A Mendoza-Caamal, Elvia %A Ginger A Metcalf %A Mi, Xuenan %A Mohlke, Karen L %A Montasser, May E %A Moon, Jee-Young %A Moreno-Macias, Hortensia %A Morrison, Alanna C %A Donna M Muzny %A Nelson, Sarah C %A Nilsson, Peter M %A O'Connell, Jeffrey R %A Orho-Melander, Marju %A Orozco, Lorena %A Palmer, Colin N A %A Palmer, Nicholette D %A Park, Cheol Joo %A Park, Kyong Soo %A Pedersen, Oluf %A Peralta, Juan M %A Peyser, Patricia A %A Post, Wendy S %A Preuss, Michael %A Psaty, Bruce M %A Qi, Qibin %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Revilla-Monsalve, Cristina %A Rich, Stephen S %A Samani, Nilesh %A Schunkert, Heribert %A Schurmann, Claudia %A Seo, Daekwan %A Seo, Jeong-Sun %A Sim, Xueling %A Sladek, Rob %A Small, Kerrin S %A So, Wing Yee %A Stilp, Adrienne M %A Tai, E Shyong %A Tam, Claudia H T %A Taylor, Kent D %A Teo, Yik Ying %A Thameem, Farook %A Tomlinson, Brian %A Tsai, Michael Y %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Tusie-Luna, Teresa %A Udler, Miriam S %A van Dam, Rob M %A Vasan, Ramachandran S %A Viaud Martinez, Karine A %A Wang, Fei Fei %A Wang, Xuzhi %A Watkins, Hugh %A Weeks, Daniel E %A Wilson, James G %A Witte, Daniel R %A Wong, Tien-Yin %A Yanek, Lisa R %A Kathiresan, Sekar %A Rader, Daniel J %A Rotter, Jerome I %A Boehnke, Michael %A McCarthy, Mark I %A Willer, Cristen J %A Natarajan, Pradeep %A Flannick, Jason A %A Khera, Amit V %A Peloso, Gina M %K Alleles %K Blood Glucose %K Case-Control Studies %K Computational Biology %K Databases, Genetic %K Diabetes Mellitus, Type 2 %K Exome %K Genetic Predisposition to Disease %K Genetic Variation %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Lipid Metabolism %K Lipids %K Liver %K Molecular Sequence Annotation %K Multifactorial Inheritance %K Open Reading Frames %K Phenotype %K Polymorphism, Single Nucleotide %X

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

%B Am J Hum Genet %V 109 %P 81-96 %8 2022 Jan 06 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34932938?dopt=Abstract %R 10.1016/j.ajhg.2021.11.021 %0 Journal Article %J Am J Hum Genet %D 2022 %T TOP-LD: A tool to explore linkage disequilibrium with TOPMed whole-genome sequence data. %A Huang, Le %A Rosen, Jonathan D %A Sun, Quan %A Chen, Jiawen %A Wheeler, Marsha M %A Zhou, Ying %A Min, Yuan-I %A Kooperberg, Charles %A Conomos, Matthew P %A Stilp, Adrienne M %A Rich, Stephen S %A Rotter, Jerome I %A Manichaikul, Ani %A Loos, Ruth J F %A Kenny, Eimear E %A Blackwell, Thomas W %A Smith, Albert V %A Jun, Goo %A Fritz J Sedlazeck %A Ginger A Metcalf %A Eric Boerwinkle %A Raffield, Laura M %A Reiner, Alex P %A Auer, Paul L %A Li, Yun %K Asian People %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %K Precision Medicine %K Whole Genome Sequencing %X

Current publicly available tools that allow rapid exploration of linkage disequilibrium (LD) between markers (e.g., HaploReg and LDlink) are based on whole-genome sequence (WGS) data from 2,504 individuals in the 1000 Genomes Project. Here, we present TOP-LD, an online tool to explore LD inferred with high-coverage (∼30×) WGS data from 15,578 individuals in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. TOP-LD provides a significant upgrade compared to current LD tools, as the TOPMed WGS data provide a more comprehensive representation of genetic variation than the 1000 Genomes data, particularly for rare variants and in the specific populations that we analyzed. For example, TOP-LD encompasses LD information for 150.3, 62.2, and 36.7 million variants for European, African, and East Asian ancestral samples, respectively, offering 2.6- to 9.1-fold increase in variant coverage compared to HaploReg 4.0 or LDlink. In addition, TOP-LD includes tens of thousands of structural variants (SVs). We demonstrate the value of TOP-LD in fine-mapping at the GGT1 locus associated with gamma glutamyltransferase in the African ancestry participants in UK Biobank. Beyond fine-mapping, TOP-LD can facilitate a wide range of applications that are based on summary statistics and estimates of LD. TOP-LD is freely available online.

%B Am J Hum Genet %V 109 %P 1175-1181 %8 2022 Jun 02 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/35504290?dopt=Abstract %R 10.1016/j.ajhg.2022.04.006 %0 Journal Article %J Genome Biol %D 2022 %T Truvari: refined structural variant comparison preserves allelic diversity. %A English, Adam C %A Menon, Vipin K %A Richard A Gibbs %A Ginger A Metcalf %A Fritz J Sedlazeck %K Algorithms %K Alleles %K Benchmarking %K Gene Frequency %K Genome, Human %K Genomic Structural Variation %K High-Throughput Nucleotide Sequencing %K Humans %X

The fundamental challenge of multi-sample structural variant (SV) analysis such as merging and benchmarking is identifying when two SVs are the same. Common approaches for comparing SVs were developed alongside technologies which produce ill-defined boundaries. As SV detection becomes more exact, algorithms to preserve this refined signal are needed. Here, we present Truvari-an SV comparison, annotation, and analysis toolkit-and demonstrate the effect of SV comparison choices by building population-level VCFs from 36 haplotype-resolved long-read assemblies. We observe over-merging from other SV merging approaches which cause up to a 2.2× inflation of allele frequency, relative to Truvari.

%B Genome Biol %V 23 %P 271 %8 2022 Dec 27 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/36575487?dopt=Abstract %R 10.1186/s13059-022-02840-6 %0 Journal Article %J Nat Commun %D 2022 %T Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program. %A Wheeler, Marsha M %A Stilp, Adrienne M %A Rao, Shuquan %A Halldórsson, Bjarni V %A Beyter, Doruk %A Wen, Jia %A Mihkaylova, Anna V %A McHugh, Caitlin P %A Lane, John %A Jiang, Min-Zhi %A Raffield, Laura M %A Jun, Goo %A Fritz J Sedlazeck %A Ginger A Metcalf %A Yao, Yao %A Bis, Joshua B %A Chami, Nathalie %A de Vries, Paul S %A Desai, Pinkal %A Floyd, James S %A Gao, Yan %A Kammers, Kai %A Kim, Wonji %A Moon, Jee-Young %A Ratan, Aakrosh %A Yanek, Lisa R %A Almasy, Laura %A Becker, Lewis C %A Blangero, John %A Cho, Michael H %A Curran, Joanne E %A Fornage, Myriam %A Kaplan, Robert C %A Lewis, Joshua P %A Loos, Ruth J F %A Mitchell, Braxton D %A Morrison, Alanna C %A Preuss, Michael %A Psaty, Bruce M %A Rich, Stephen S %A Rotter, Jerome I %A Tang, Hua %A Tracy, Russell P %A Eric Boerwinkle %A Abecasis, Gonçalo R %A Blackwell, Thomas W %A Smith, Albert V %A Johnson, Andrew D %A Mathias, Rasika A %A Nickerson, Deborah A %A Conomos, Matthew P %A Li, Yun %A Þorsteinsdóttir, Unnur %A Magnússon, Magnús K %A Stefansson, Kari %A Pankratz, Nathan D %A Bauer, Daniel E %A Auer, Paul L %A Reiner, Alex P %K Blood Cells %K Genome-Wide Association Study %K Humans %K Whole Genome Sequencing %X

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

%B Nat Commun %V 13 %P 7592 %8 2022 Dec 08 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/36481753?dopt=Abstract %R 10.1038/s41467-022-35354-7 %0 Journal Article %J Hum Mol Genet %D 2022 %T Whole-exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors. %A Pankratz, Nathan %A Wei, Peng %A Brody, Jennifer A %A Chen, Ming-Huei %A de Vries, Paul S %A Huffman, Jennifer E %A Stimson, Mary Rachel %A Auer, Paul L %A Eric Boerwinkle %A Cushman, Mary %A de Maat, Moniek P M %A Folsom, Aaron R %A Franco, Oscar H %A Richard A Gibbs %A Haagenson, Kelly K %A Hofman, Albert %A Johnsen, Jill M %A Kovar, Christie L %A Kraaij, Robert %A McKnight, Barbara %A Ginger A Metcalf %A Donna M Muzny %A Psaty, Bruce M %A Tang, Weihong %A Uitterlinden, André G %A van Rooij, Jeroen G J %A Dehghan, Abbas %A O'Donnell, Christopher J %A Reiner, Alex P %A Morrison, Alanna C %A Smith, Nicholas L %K Exome Sequencing %K Factor VII %K Factor VIII %K Fibrinogen %K Hemostatics %K Humans %K Polymorphism, Single Nucleotide %K von Willebrand Factor %X

Plasma levels of fibrinogen, coagulation factors VII and VIII and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole-exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and the National Heart, Lung and Blood Institute's Exome Sequencing Project. Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5%) in fibrinogen gamma chain (FGG) (with fibrinogen, P = 9.1 × 10-13), coagulation factor VII (F7) (with factor VII, P = 1.3 × 10-72; seven novel variants) and VWF (with factor VIII and vWF; P = 3.2 × 10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; P = 4.2 × 10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to AAs (rs3211938) in CD36 molecule (CD36). This variant has previously been linked to dyslipidemia but not with the levels of a hemostatic factor. These efforts represent the largest integration of whole-exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.

%B Hum Mol Genet %V 31 %P 3120-3132 %8 2022 Sep 10 %G eng %N 18 %1 https://www.ncbi.nlm.nih.gov/pubmed/35552711?dopt=Abstract %R 10.1093/hmg/ddac100 %0 Journal Article %J Genome Med %D 2022 %T Whole-genome sequencing as an investigational device for return of hereditary disease risk and pharmacogenomic results as part of the All of Us Research Program. %A Eric Venner %A Donna M Muzny %A Smith, Joshua D %A Kimberly Walker %A Neben, Cynthia L %A Lockwood, Christina M %A Empey, Phillip E %A Ginger A Metcalf %A Kachulis, Chris %A Mian, Sana %A Musick, Anjene %A Rehm, Heidi L %A Harrison, Steven %A Gabriel, Stacey %A Richard A Gibbs %A Nickerson, Deborah %A Zhou, Alicia Y %A Doheny, Kimberly %A Ozenberger, Bradley %A Topper, Scott E %A Lennon, Niall J %K Genomics %K Humans %K Pharmacogenetics %K Population Health %K United States %K Whole Genome Sequencing %X

BACKGROUND: The All of Us Research Program (AoURP, "the program") is an initiative, sponsored by the National Institutes of Health (NIH), that aims to enroll one million people (or more) across the USA. Through repeated engagement of participants, a research resource is being created to enable a variety of future observational and interventional studies. The program has also committed to genomic data generation and returning important health-related information to participants.

METHODS: Whole-genome sequencing (WGS), variant calling processes, data interpretation, and return-of-results procedures had to be created and receive an Investigational Device Exemption (IDE) from the United States Food and Drug Administration (FDA). The performance of the entire workflow was assessed through the largest known cross-center, WGS-based, validation activity that was refined iteratively through interactions with the FDA over many months.

RESULTS: The accuracy and precision of the WGS process as a device for the return of certain health-related genomic results was determined to be sufficient, and an IDE was granted.

CONCLUSIONS: We present here both the process of navigating the IDE application process with the FDA and the results of the validation study as a guide to future projects which may need to follow a similar path. Changes to the program in the future will be covered in supplementary submissions to the IDE and will support additional variant classes, sample types, and any expansion to the reportable regions.

%B Genome Med %V 14 %P 34 %8 2022 Mar 28 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/35346344?dopt=Abstract %R 10.1186/s13073-022-01031-z %0 Journal Article %J Gigascience %D 2022 %T xAtlas: scalable small variant calling across heterogeneous next-generation sequencing experiments. %A Farek, Jesse %A Hughes, Daniel %A Salerno, William %A Zhu, Yiming %A Pisupati, Aishwarya %A Mansfield, Adam %A Krasheninina, Olga %A English, Adam C %A Ginger A Metcalf %A Eric Boerwinkle %A Donna M Muzny %A Richard A Gibbs %A Ziad Khan %A Fritz J Sedlazeck %K Algorithms %K Genome %K High-Throughput Nucleotide Sequencing %K INDEL Mutation %K Polymorphism, Single Nucleotide %K Software %X

BACKGROUND: The growing volume and heterogeneity of next-generation sequencing (NGS) data complicate the further optimization of identifying DNA variation, especially considering that curated high-confidence variant call sets frequently used to validate these methods are generally developed from the analysis of comparatively small and homogeneous sample sets.

FINDINGS: We have developed xAtlas, a single-sample variant caller for single-nucleotide variants (SNVs) and small insertions and deletions (indels) in NGS data. xAtlas features rapid runtimes, support for CRAM and gVCF file formats, and retraining capabilities. xAtlas reports SNVs with 99.11% recall and 98.43% precision across a reference HG002 sample at 60× whole-genome coverage in less than 2 CPU hours. Applying xAtlas to 3,202 samples at 30× whole-genome coverage from the 1000 Genomes Project achieves an average runtime of 1.7 hours per sample and a clear separation of the individual populations in principal component analysis across called SNVs.

CONCLUSIONS: xAtlas is a fast, lightweight, and accurate SNV and small indel calling method. Source code for xAtlas is available under a BSD 3-clause license at https://github.com/jfarek/xatlas.

%B Gigascience %V 12 %8 2022 Dec 28 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/36644891?dopt=Abstract %R 10.1093/gigascience/giac125 %0 Journal Article %J Nature %D 2021 %T Author Correction: High-depth African genomes inform human migration and health. %A Choudhury, Ananyo %A Aron, Shaun %A Botigué, Laura R %A Sengupta, Dhriti %A Botha, Gerrit %A Bensellak, Taoufik %A Wells, Gordon %A Kumuthini, Judit %A Shriner, Daniel %A Fakim, Yasmina J %A Ghoorah, Anisah W %A Dareng, Eileen %A Odia, Trust %A Falola, Oluwadamilare %A Adebiyi, Ezekiel %A Hazelhurst, Scott %A Mazandu, Gaston %A Nyangiri, Oscar A %A Mbiyavanga, Mamana %A Benkahla, Alia %A Kassim, Samar K %A Mulder, Nicola %A Adebamowo, Sally N %A Chimusa, Emile R %A Donna M Muzny %A Ginger A Metcalf %A Richard A Gibbs %A Rotimi, Charles %A Ramsay, Michèle %A Adeyemo, Adebowale A %A Lombard, Zané %A Hanchard, Neil A %B Nature %V 592 %P E26 %8 2021 Apr %G eng %N 7856 %1 https://www.ncbi.nlm.nih.gov/pubmed/33846614?dopt=Abstract %R 10.1038/s41586-021-03286-9 %0 Journal Article %J Nat Commun %D 2021 %T Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices. %A Natarajan, Pradeep %A Pampana, Akhil %A Graham, Sarah E %A Ruotsalainen, Sanni E %A Perry, James A %A de Vries, Paul S %A Broome, Jai G %A Pirruccello, James P %A Honigberg, Michael C %A Aragam, Krishna %A Wolford, Brooke %A Brody, Jennifer A %A Antonacci-Fulton, Lucinda %A Arden, Moscati %A Aslibekyan, Stella %A Assimes, Themistocles L %A Ballantyne, Christie M %A Bielak, Lawrence F %A Bis, Joshua C %A Cade, Brian E %A Do, Ron %A Harshavardhan Doddapaneni %A Emery, Leslie S %A Hung, Yi-Jen %A Irvin, Marguerite R %A Khan, Alyna T %A Lange, Leslie %A Lee, Jiwon %A Lemaitre, Rozenn N %A Martin, Lisa W %A Ginger A Metcalf %A Montasser, May E %A Moon, Jee-Young %A Donna M Muzny %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Peralta, Juan M %A Peyser, Patricia A %A Stilp, Adrienne M %A Tsai, Michael %A Wang, Fei Fei %A Weeks, Daniel E %A Yanek, Lisa R %A Wilson, James G %A Abecasis, Goncalo %A Arnett, Donna K %A Becker, Lewis C %A Blangero, John %A Eric Boerwinkle %A Bowden, Donald W %A Chang, Yi-Cheng %A Chen, Yii-Der I %A Choi, Won Jung %A Correa, Adolfo %A Curran, Joanne E %A Daly, Mark J %A Dutcher, Susan K %A Ellinor, Patrick T %A Fornage, Myriam %A Freedman, Barry I %A Gabriel, Stacey %A Germer, Soren %A Richard A Gibbs %A He, Jiang %A Hveem, Kristian %A Jarvik, Gail P %A Kaplan, Robert C %A Kardia, Sharon L R %A Kenny, Eimear %A Kim, Ryan W %A Kooperberg, Charles %A Laurie, Cathy C %A Lee, Seonwook %A Lloyd-Jones, Don M %A Loos, Ruth J F %A Lubitz, Steven A %A Mathias, Rasika A %A Martinez, Karine A Viaud %A McGarvey, Stephen T %A Mitchell, Braxton D %A Nickerson, Deborah A %A North, Kari E %A Palotie, Aarno %A Park, Cheol Joo %A Psaty, Bruce M %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Seo, Daekwan %A Seo, Jeong-Sun %A Smith, Albert V %A Tracy, Russell P %A Vasan, Ramachandran S %A Kathiresan, Sekar %A Cupples, L Adrienne %A Rotter, Jerome I %A Morrison, Alanna C %A Rich, Stephen S %A Ripatti, Samuli %A Willer, Cristen %A Peloso, Gina M %K Cardiometabolic Risk Factors %K Chromosomes, Human, X %K Eye Proteins %K Female %K Gene Expression Regulation %K Genetic Association Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genotype %K Humans %K Lipids %K Male %K Middle Aged %K Nerve Tissue Proteins %K Phenomics %K Polymorphism, Single Nucleotide %K Subcutaneous Tissue %K Whole Genome Sequencing %X

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

%B Nat Commun %V 12 %P 2182 %8 2021 Apr 12 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33846329?dopt=Abstract %R 10.1038/s41467-021-22339-1 %0 Journal Article %J Genet Med %D 2021 %T Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications. %A David R Murdock %A Eric Venner %A Donna M Muzny %A Ginger A Metcalf %A Mullai Murugan %A Hadley, Trevor D %A Chander, Varuna %A de Vries, Paul S %A Jia, Xiaoming %A Hussain, Aliza %A Agha, Ali M %A Aniko Sabo %A Li, Shoudong %A Meng, Qingchang %A Jianhong Hu %A Tian, Xia %A Cohen, Michelle %A Yi, Victoria %A Kovar, Christie L %A Marie-Claude Gingras %A Korchina, Viktoriya %A Howard, Chad %A Riconda, Daniel L %A Pereira, Stacey %A Smith, Hadley S %A Huda, Zohra A %A Buentello, Alexandria %A Marino, Patricia R %A Leiber, Lee %A Balasubramanyam, Ashok %A Amos, Christopher I %A Civitello, Andrew B %A Chelu, Mihail G %A Maag, Ronald %A McGuire, Amy L %A Eric Boerwinkle %A Wehrens, Xander H T %A Ballantyne, Christie M %A Richard A Gibbs %K Adult %K Cardiology %K Cardiovascular Diseases %K Genetic Testing %K Humans %K Pharmacogenetics %K Pharmacogenomic Testing %K United States %X

PURPOSE: Cardiovascular disease (CVD) is the leading cause of death in adults in the United States, yet the benefits of genetic testing are not universally accepted.

METHODS: We developed the "HeartCare" panel of genes associated with CVD, evaluating high-penetrance Mendelian conditions, coronary artery disease (CAD) polygenic risk, LPA gene polymorphisms, and specific pharmacogenetic (PGx) variants. We enrolled 709 individuals from cardiology clinics at Baylor College of Medicine, and samples were analyzed in a CAP/CLIA-certified laboratory. Results were returned to the ordering physician and uploaded to the electronic medical record.

RESULTS: Notably, 32% of patients had a genetic finding with clinical management implications, even after excluding PGx results, including 9% who were molecularly diagnosed with a Mendelian condition. Among surveyed physicians, 84% reported medical management changes based on these results, including specialist referrals, cardiac tests, and medication changes. LPA polymorphisms and high polygenic risk of CAD were found in 20% and 9% of patients, respectively, leading to diet, lifestyle, and other changes. Warfarin and simvastatin pharmacogenetic variants were present in roughly half of the cohort.

CONCLUSION: Our results support the use of genetic information in routine cardiovascular health management and provide a roadmap for accompanying research.

%B Genet Med %V 23 %P 2404-2414 %8 2021 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/34363016?dopt=Abstract %R 10.1038/s41436-021-01294-8 %0 Journal Article %J JMIR Res Protoc %D 2021 %T The Implementation Science for Genomic Health Translation (INSIGHT) Study in Epilepsy: Protocol for a Learning Health Care System. %A Feofanova, Elena Valeryevna %A Zhang, Guo-Qiang %A Lhatoo, Samden %A Ginger A Metcalf %A Eric Boerwinkle %A Eric Venner %X

BACKGROUND: Genomic medicine is poised to improve care for common complex diseases such as epilepsy, but additional clinical informatics and implementation science research is needed for it to become a part of the standard of care. Epilepsy is an exemplary complex neurological disorder for which DNA diagnostics have shown to be advantageous for patient care.

OBJECTIVE: We designed the Implementation Science for Genomic Health Translation (INSIGHT) study to leverage the fact that both the clinic and testing laboratory control the development and customization of their respective electronic health records and clinical reporting platforms. Through INSIGHT, we can rapidly prototype and benchmark novel approaches to incorporating clinical genomics into patient care. Of particular interest are clinical decision support tools that take advantage of domain knowledge from clinical genomics and can be rapidly adjusted based on feedback from clinicians.

METHODS: Building on previously developed evidence and infrastructure components, our model includes the following: establishment of an intervention-ready genomic knowledge base for patient care, creation of a health informatics platform and linking it to a clinical genomics reporting system, and scaling and evaluation of INSIGHT following established implementation science principles.

RESULTS: INSIGHT was approved by the Institutional Review Board at the University of Texas Health Science Center at Houston on May 15, 2020, and is designed as a 2-year proof-of-concept study beginning in December 2021. By design, 120 patients from the Texas Comprehensive Epilepsy Program are to be enrolled to test the INSIGHT workflow. Initial results are expected in the first half of 2023.

CONCLUSIONS: INSIGHT's domain-specific, practical but generalizable approach may help catalyze a pathway to accelerate translation of genomic knowledge into impactful interventions in patient care.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/25576.

%B JMIR Res Protoc %V 10 %P e25576 %8 2021 Mar 26 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/33769305?dopt=Abstract %R 10.2196/25576 %0 Journal Article %J Bioinformatics %D 2021 %T muCNV: Genotyping Structural Variants for Population-level Sequencing. %A Jun, Goo %A Fritz J Sedlazeck %A Zhu, Qihui %A English, Adam %A Ginger A Metcalf %A Kang, Hyun Min %A Lee, Charles %A Richard A Gibbs %A Eric Boerwinkle %X

MOTIVATION: There are high demands for joint genotyping of structural variations with short-read sequencing, but efficient and accurate genotyping in population scale is a challenging task.

RESULTS: We developed muCNV that aggregates per-sample summary pileups for joint genotyping of > 100,000 samples. Pilot results show very low Mendelian inconsistencies. Applications to large-scale projects in cloud show the computational efficiencies of muCNV genotyping pipeline.

AVAILABILITY: muCNV is publicly available for download at: https://github.com/gjun/muCNV.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

%B Bioinformatics %V 37 %P 2055-7 %8 2021 Mar 24 %G eng %N 14 %1 https://www.ncbi.nlm.nih.gov/pubmed/33760063?dopt=Abstract %R 10.1093/bioinformatics/btab199 %0 Journal Article %J PLoS One %D 2021 %T Oligonucleotide capture sequencing of the SARS-CoV-2 genome and subgenomic fragments from COVID-19 individuals. %A Harshavardhan Doddapaneni %A Cregeen, Sara Javornik %A Sucgang, Richard %A Meng, Qingchang %A Xiang Qin %A Avadhanula, Vasanthi %A Chao, Hsu %A Menon, Vipin %A Nicholson, Erin %A Henke, David %A Piedra, Felipe-Andres %A Rajan, Anubama %A Momin, Zeineen %A Kottapalli, Kavya %A Hoffman, Kristi L %A Fritz J Sedlazeck %A Ginger A Metcalf %A Piedra, Pedro A %A Donna M Muzny %A Petrosino, Joseph F %A Richard A Gibbs %K COVID-19 %K DNA, Complementary %K Gene Frequency %K Genetic Variation %K Genome, Viral %K Humans %K Open Reading Frames %K Real-Time Polymerase Chain Reaction %K RNA, Viral %K SARS-CoV-2 %K Sequence Analysis, DNA %K Viral Load %X

The newly emerged and rapidly spreading SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). To facilitate a deeper understanding of the viral biology we developed a capture sequencing methodology to generate SARS-CoV-2 genomic and transcriptome sequences from infected patients. We utilized an oligonucleotide probe-set representing the full-length genome to obtain both genomic and transcriptome (subgenomic open reading frames [ORFs]) sequences from 45 SARS-CoV-2 clinical samples with varying viral titers. For samples with higher viral loads (cycle threshold value under 33, based on the CDC qPCR assay) complete genomes were generated. Analysis of junction reads revealed regions of differential transcriptional activity among samples. Mixed allelic frequencies along the 20kb ORF1ab gene in one sample, suggested the presence of a defective viral RNA species subpopulation maintained in mixture with functional RNA in one sample. The associated workflow is straightforward, and hybridization-based capture offers an effective and scalable approach for sequencing SARS-CoV-2 from patient samples.

%B PLoS One %V 16 %P e0244468 %8 2021 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/34432798?dopt=Abstract %R 10.1371/journal.pone.0244468 %0 Journal Article %J BMC Med %D 2021 %T Transmission event of SARS-CoV-2 delta variant reveals multiple vaccine breakthrough infections. %A Farinholt, Timothy %A Harshavardhan Doddapaneni %A Xiang Qin %A Menon, Vipin %A Meng, Qingchang %A Ginger A Metcalf %A Chao, Hsu %A Marie-Claude Gingras %A Avadhanula, Vasanthi %A Farinholt, Paige %A Agrawal, Charu %A Donna M Muzny %A Piedra, Pedro A %A Richard A Gibbs %A Petrosino, Joseph %K BNT162 Vaccine %K COVID-19 %K COVID-19 Vaccines %K Humans %K Immune Evasion %K SARS-CoV-2 %X

BACKGROUND: This study aims to identify the causative strain of SARS-CoV-2 in a cluster of vaccine breakthroughs. Vaccine breakthrough by a highly transmissible SARS-CoV-2 strain is a risk to global public health.

METHODS: Nasopharyngeal swabs from suspected vaccine breakthrough cases were tested for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) by qPCR (quantitative polymerase chain reaction) for Wuhan-Hu1 and alpha variant. Positive samples were then sequenced by Swift Normalase Amplicon Panels to determine the causal variant. GATK (genome analysis toolkit) variants were filtered with allele fraction ≥80 and min read depth 30x.

RESULTS: Viral sequencing revealed an infection cluster of 6 vaccinated patients infected with the delta (B.1.617.2) SARS-CoV-2 variant. With no history of vaccine breakthrough, this suggests the delta variant may possess immune evasion in patients that received the Pfizer BNT162b2, Moderna mRNA-1273, and Covaxin BBV152.

CONCLUSIONS: Delta variant may pose the highest risk out of any currently circulating SARS-CoV-2 variants, with previously described increased transmissibility over alpha variant and now, possible vaccine breakthrough.

FUNDING: Parts of this work was supported by the National Institute of Allergy and Infectious Diseases (1U19AI144297) and Baylor College of Medicine internal funding.

%B BMC Med %V 19 %P 255 %8 2021 Oct 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/34593004?dopt=Abstract %R 10.1186/s12916-021-02103-4 %0 Journal Article %J medRxiv %D 2021 %T Transmission event of SARS-CoV-2 Delta variant reveals multiple vaccine breakthrough infections. %A Farinholt, Timothy %A Harshavardhan Doddapaneni %A Xiang Qin %A Menon, Vipin %A Meng, Qingchang %A Ginger A Metcalf %A Chao, Hsu %A Marie-Claude Gingras %A Farinholt, Paige %A Agrawal, Charu %A Donna M Muzny %A Piedra, Pedro A %A Richard A Gibbs %A Petrosino, Joseph %X

IMPORTANCE: Vaccine breakthrough by an emergent SARS-CoV-2 variant poses a great risk to global public health.

OBJECTIVE: To determine the SARS-CoV-2 variant responsible for 6 cases of vaccine breakthrough.

DESIGN: Nasopharyngeal swabs from suspected vaccine breakthrough cases were tested for SARS-CoV-2 by qPCR for Wuhan-Hu1 and Alpha variant. Positive samples were then sequenced by Swift Normalase Amplicon Panels to determine the causal variant.

SETTING: Transmission event occurred at events surrounding a wedding outside of Houston, TX. Two patients from India, likely transmitted the Delta variant to other guests.

PARTICIPANTS: Following a positive SARS-CoV-2 qPCR test at a third-party site, six fully vaccinated patients were investigated. Three males and three females ranged from 53 to 69 years old. One patient suffered from diabetes while three others were classified as overweight. No significant other comorbidities were identified. None of the patients had a history of failed vaccination.

KEY POINTS: Which SARS-CoV-2 variant is responsible for 6 cases of vaccine breakthrough, one interventional monoclonal antibody treatment, and one death? Viral sequencing revealed 6 vaccinated patients were infected with the Delta SARS-CoV-2 variant. With no histories of vaccine breakthrough, this suggests Delta variant may possess immune evasion in patients that received the Pfizer BNT162b2, Moderna mRNA-1273, and Covaxin BBV152. Delta variant may pose the highest risk out of any currently circulating SARS-CoV-2 variants, with increased transmissibility over Alpha variant and possible vaccine breakthrough.

%B medRxiv %8 2021 Jul 12 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/34268529?dopt=Abstract %R 10.1101/2021.06.28.21258780 %0 Journal Article %J Am J Hum Genet %D 2020 %T Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts. %A Raffield, Laura M %A Iyengar, Apoorva K %A Wang, Biqi %A Gaynor, Sheila M %A Spracklen, Cassandra N %A Zhong, Xue %A Kowalski, Madeline H %A Salimi, Shabnam %A Polfus, Linda M %A Benjamin, Emelia J %A Bis, Joshua C %A Bowler, Russell %A Cade, Brian E %A Choi, Won Jung %A Comellas, Alejandro P %A Correa, Adolfo %A Cruz, Pedro %A Harshavardhan Doddapaneni %A Durda, Peter %A Gogarten, Stephanie M %A Jain, Deepti %A Kim, Ryan W %A Kral, Brian G %A Lange, Leslie A %A Larson, Martin G %A Laurie, Cecelia %A Lee, Jiwon %A Lee, Seonwook %A Lewis, Joshua P %A Ginger A Metcalf %A Mitchell, Braxton D %A Momin, Zeineen %A Donna M Muzny %A Pankratz, Nathan %A Park, Cheol Joo %A Rich, Stephen S %A Rotter, Jerome I %A Ryan, Kathleen %A Seo, Daekwan %A Tracy, Russell P %A Viaud-Martinez, Karine A %A Yanek, Lisa R %A Zhao, Lue Ping %A Lin, Xihong %A Li, Bingshan %A Li, Yun %A Dupuis, Josée %A Reiner, Alexander P %A Mohlke, Karen L %A Auer, Paul L %K Asian People %K Black People %K C-Reactive Protein %K Cohort Studies %K Gene Frequency %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %K White People %K Whole Genome Sequencing %X

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (∼10% and ∼1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.

%B Am J Hum Genet %V 106 %P 112-120 %8 2020 Jan 02 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31883642?dopt=Abstract %R 10.1016/j.ajhg.2019.12.002 %0 Journal Article %J Nature %D 2020 %T High-depth African genomes inform human migration and health. %A Choudhury, Ananyo %A Aron, Shaun %A Botigué, Laura R %A Sengupta, Dhriti %A Botha, Gerrit %A Bensellak, Taoufik %A Wells, Gordon %A Kumuthini, Judit %A Shriner, Daniel %A Fakim, Yasmina J %A Ghoorah, Anisah W %A Dareng, Eileen %A Odia, Trust %A Falola, Oluwadamilare %A Adebiyi, Ezekiel %A Hazelhurst, Scott %A Mazandu, Gaston %A Nyangiri, Oscar A %A Mbiyavanga, Mamana %A Benkahla, Alia %A Kassim, Samar K %A Mulder, Nicola %A Adebamowo, Sally N %A Chimusa, Emile R %A Donna M Muzny %A Ginger A Metcalf %A Richard A Gibbs %A Rotimi, Charles %A Ramsay, Michèle %A Adeyemo, Adebowale A %A Lombard, Zané %A Hanchard, Neil A %K Africa %K Datasets as Topic %K DNA Repair %K Female %K Gene Flow %K Genetic Variation %K Genetics, Medical %K Genetics, Population %K Genome, Human %K Genomics %K Health %K History, Ancient %K Human Migration %K Humans %K Immunity %K Language %K Male %K Metabolism %K Selection, Genetic %K Whole Genome Sequencing %X

The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity among African individuals has been surveyed. Here we performed whole-genome sequencing analyses of 426 individuals-comprising 50 ethnolinguistic groups, including previously unsampled populations-to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon-but in other genes, variants denoted as 'likely pathogenic' in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health.

%B Nature %V 586 %P 741-748 %8 2020 Oct %G eng %N 7831 %1 https://www.ncbi.nlm.nih.gov/pubmed/33116287?dopt=Abstract %R 10.1038/s41586-020-2859-7 %0 Journal Article %J bioRxiv %D 2020 %T Oligonucleotide Capture Sequencing of the SARS-CoV-2 Genome and Subgenomic Fragments from COVID-19 Individuals. %A Harshavardhan Doddapaneni %A Cregeen, Sara Javornik %A Sucgang, Richard %A Meng, Qingchang %A Xiang Qin %A Avadhanula, Vasanthi %A Chao, Hsu %A Menon, Vipin %A Nicholson, Erin %A Henke, David %A Piedra, Felipe-Andres %A Rajan, Anubama %A Momin, Zeineen %A Kottapalli, Kavya %A Hoffman, Kristi L %A Fritz J Sedlazeck %A Ginger A Metcalf %A Piedra, Pedro A %A Donna M Muzny %A Petrosino, Joseph F %A Richard A Gibbs %X

The newly emerged and rapidly spreading SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). To facilitate a deeper understanding of the viral biology we developed a capture sequencing methodology to generate SARS-CoV-2 genomic and transcriptome sequences from infected patients. We utilized an oligonucleotide probe-set representing the full-length genome to obtain both genomic and transcriptome (subgenomic open reading frames [ORFs]) sequences from 45 SARS-CoV-2 clinical samples with varying viral titers. For samples with higher viral loads (cycle threshold value under 33, based on the CDC qPCR assay) complete genomes were generated. Analysis of junction reads revealed regions of differential transcriptional activity and provided evidence of expression of ORF10. Heterogeneous allelic frequencies along the 20kb ORF1ab gene suggested the presence of a defective interfering viral RNA species subpopulation in one sample. The associated workflow is straightforward, and hybridization-based capture offers an effective and scalable approach for sequencing SARS-CoV-2 from patient samples.

%B bioRxiv %8 2020 Dec 11 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/33330863?dopt=Abstract %R 10.1101/2020.12.11.421057 %0 Journal Article %J bioRxiv %D 2020 %T Oligonucleotide capture sequencing of the SARS-CoV-2 genome and subgenomic fragments from COVID-19 individuals. %A Harshavardhan Doddapaneni %A Cregeen, Sara Javornik %A Sucgang, Richard %A Meng, Qingchang %A Xiang Qin %A Avadhanula, Vasanthi %A Chao, Hsu %A Menon, Vipin %A Nicholson, Erin %A Henke, David %A Piedra, Felipe-Andres %A Rajan, Anubama %A Momin, Zeineen %A Kottapalli, Kavya %A Hoffman, Kristi L %A Fritz J Sedlazeck %A Ginger A Metcalf %A Piedra, Pedro A %A Donna M Muzny %A Petrosino, Joseph F %A Richard A Gibbs %X

The newly emerged and rapidly spreading SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). To facilitate a deeper understanding of the viral biology we developed a capture sequencing methodology to generate SARS-CoV-2 genomic and transcriptome sequences from infected patients. We utilized an oligonucleotide probe-set representing the full-length genome to obtain both genomic and transcriptome (subgenomic open reading frames [ORFs]) sequences from 45 SARS-CoV-2 clinical samples with varying viral titers. For samples with higher viral loads (cycle threshold value under 33, based on the CDC qPCR assay) complete genomes were generated. Analysis of junction reads revealed regions of differential transcriptional activity and provided evidence of expression of ORF10. Heterogeneous allelic frequencies along the 20kb ORF1ab gene suggested the presence of a defective interfering viral RNA species subpopulation in one sample. The associated workflow is straightforward, and hybridization-based capture offers an effective and scalable approach for sequencing SARS-CoV-2 from patient samples.

%B bioRxiv %8 2020 Jul 27 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/32766579?dopt=Abstract %R 10.1101/2020.07.27.223495 %0 Journal Article %J Nat Commun %D 2020 %T Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants. %A Zhao, Xutong %A Qiao, Dandi %A Yang, Chaojie %A Kasela, Silva %A Kim, Wonji %A Ma, Yanlin %A Shrine, Nick %A Batini, Chiara %A Sofer, Tamar %A Taliun, Sarah A Gagliano %A Sakornsakolpat, Phuwanat %A Balte, Pallavi P %A Prokopenko, Dmitry %A Yu, Bing %A Lange, Leslie A %A Dupuis, Josée %A Cade, Brian E %A Lee, Jiwon %A Gharib, Sina A %A Daya, Michelle %A Laurie, Cecelia A %A Ruczinski, Ingo %A Cupples, L Adrienne %A Loehr, Laura R %A Bartz, Traci M %A Morrison, Alanna C %A Psaty, Bruce M %A Vasan, Ramachandran S %A Wilson, James G %A Taylor, Kent D %A Durda, Peter %A Johnson, W Craig %A Cornell, Elaine %A Guo, Xiuqing %A Liu, Yongmei %A Tracy, Russell P %A Ardlie, Kristin G %A Aguet, Francois %A VanDenBerg, David J %A Papanicolaou, George J %A Rotter, Jerome I %A Barnes, Kathleen C %A Jain, Deepti %A Nickerson, Deborah A %A Donna M Muzny %A Ginger A Metcalf %A Harshavardhan Doddapaneni %A Dugan-Perez, Shannon %A Gupta, Namrata %A Gabriel, Stacey %A Rich, Stephen S %A O'Connor, George T %A Redline, Susan %A Reed, Robert M %A Laurie, Cathy C %A Daviglus, Martha L %A Preudhomme, Liana K %A Burkart, Kristin M %A Kaplan, Robert C %A Wain, Louise V %A Tobin, Martin D %A London, Stephanie J %A Lappalainen, Tuuli %A Oelsner, Elizabeth C %A Abecasis, Gonçalo R %A Silverman, Edwin K %A Barr, R Graham %A Cho, Michael H %A Manichaikul, Ani %K Adult %K Aged %K Aged, 80 and over %K Alpha-Ketoglutarate-Dependent Dioxygenase FTO %K Black or African American %K Calcium-Binding Proteins %K Feasibility Studies %K Female %K Follow-Up Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Intracellular Signaling Peptides and Proteins %K Lung %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Protein Inhibitors of Activated STAT %K Pulmonary Disease, Chronic Obstructive %K Respiratory Physiological Phenomena %K Small Ubiquitin-Related Modifier Proteins %K Whole Genome Sequencing %X

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

%B Nat Commun %V 11 %P 5182 %8 2020 Oct 14 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33057025?dopt=Abstract %R 10.1038/s41467-020-18334-7 %0 Journal Article %J J Mol Diagn %D 2019 %T Leveraging Human Microbiome Features to Diagnose and Stratify Children with Irritable Bowel Syndrome. %A Hollister, Emily B %A Oezguen, Numan %A Chumpitazi, Bruno P %A Luna, Ruth Ann %A Weidler, Erica M %A Rubio-Gonzales, Michelle %A Dahdouli, Mahmoud %A Cope, Julia L %A Mistretta, Toni-Ann %A Raza, Sabeen %A Ginger A Metcalf %A Donna M Muzny %A Richard A Gibbs %A Petrosino, Joseph F %A Heitkemper, Margaret %A Savidge, Tor C %A Shulman, Robert J %A Versalovic, James %K Abdominal Pain %K Bacteria %K Case-Control Studies %K Child %K Feces %K Female %K Gastrointestinal Tract %K Genomics %K Humans %K Irritable Bowel Syndrome %K Male %K Metabolome %K Microbiota %K Multivariate Analysis %K Principal Component Analysis %K Statistics, Nonparametric %X

Accurate diagnosis and stratification of children with irritable bowel syndrome (IBS) remain challenging. Given the central role of recurrent abdominal pain in IBS, we evaluated the relationships of pediatric IBS and abdominal pain with intestinal microbes and fecal metabolites using a comprehensive clinical characterization and multiomics strategy. Using rigorous clinical phenotyping, we identified preadolescent children (aged 7 to 12 years) with Rome III IBS (n = 23) and healthy controls (n = 22) and characterized their fecal microbial communities using whole-genome shotgun metagenomics and global unbiased fecal metabolomic profiling. Correlation-based approaches and machine learning algorithms identified associations between microbes, metabolites, and abdominal pain. IBS cases differed from controls with respect to key bacterial taxa (eg, Flavonifractor plautii and Lachnospiraceae bacterium 7_1_58FAA), metagenomic functions (eg, carbohydrate metabolism and amino acid metabolism), and higher-order metabolites (eg, secondary bile acids, sterols, and steroid-like compounds). Significant associations between abdominal pain frequency and severity and intestinal microbial features were identified. A random forest classifier built on metagenomic and metabolic markers successfully distinguished IBS cases from controls (area under the curve, 0.93). Leveraging multiple lines of evidence, intestinal microbes, genes/pathways, and metabolites were associated with IBS, and these features were capable of distinguishing children with IBS from healthy children. These multi-omics features, and their links to childhood IBS coupled with nutritional interventions, may lead to new microbiome-guided diagnostic and therapeutic strategies.

%B J Mol Diagn %V 21 %P 449-461 %8 2019 May %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/31005411?dopt=Abstract %R 10.1016/j.jmoldx.2019.01.006 %0 Journal Article %J Genetics %D 2018 %T Sequence-Based Analysis of Lipid-Related Metabolites in a Multiethnic Study. %A Feofanova, Elena V %A Yu, Bing %A Ginger A Metcalf %A Liu, Xiaoming %A Donna M Muzny %A Below, Jennifer E %A Wagenknecht, Lynne E %A Richard A Gibbs %A Morrison, Alanna C %A Eric Boerwinkle %K Black or African American %K Female %K Humans %K Lipid Metabolism %K Male %K Metabolome %K Middle Aged %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K White People %X

Small molecule lipid-related metabolites are important components of fatty acid and steroid metabolism-two important contributors to human health. This study investigated the extent to which rare and common genetic variants spanning the human genome influence the lipid-related metabolome. Sequence data from 1552 European-Americans (EA) and 1872 African-Americans (AA) were analyzed to examine the impact of common and rare variants on the levels of 102 circulating lipid-related metabolites measured by a combination of chromatography and mass spectroscopy. We conducted single variant tests [minor allele frequency (MAF) > 5%, statistical significance -value ≤ 2.45 × 10] and tests aggregating rare variants (MAF ≤ 5%) across multiple genomic motifs, such as coding regions and regulatory domains, and sliding windows. Multiethnic meta-analyses detected 53 lipid-related metabolites-locus pairs, which were inspected for evidence of consistent signal between the two ethnic groups. Thirty-eight lipid-related metabolite-genomic region associations were consistent across ethnicities, among which seven were novel. The regions contain genes that are related to metabolite transport () and metabolism (, , , and ). Six of the seven novel findings lie in expression quantitative trait loci affecting the expression levels of 14 surrounding genes in multiple tissues. Imputed expression levels of 10 of the affected genes were associated with four corresponding lipid-related traits in at least one tissue. Our findings offer valuable insight into circulating lipid-related metabolite regulation in a multiethnic population.

%B Genetics %V 209 %P 607-616 %8 2018 Jun %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/29610217?dopt=Abstract %R 10.1534/genetics.118.300751 %0 Journal Article %J Nature %D 2018 %T Temporal development of the gut microbiome in early childhood from the TEDDY study. %A Stewart, Christopher J %A Ajami, Nadim J %A O'Brien, Jacqueline L %A Hutchinson, Diane S %A Smith, Daniel P %A Wong, Matthew C %A Ross, Matthew C %A Lloyd, Richard E %A Harshavardhan Doddapaneni %A Ginger A Metcalf %A Donna M Muzny %A Richard A Gibbs %A Vatanen, Tommi %A Huttenhower, Curtis %A Xavier, Ramnik J %A Rewers, Marian %A Hagopian, William %A Toppari, Jorma %A Ziegler, Anette-G %A She, Jin-Xiong %A Akolkar, Beena %A Lernmark, Ake %A Hyoty, Heikki %A Vehik, Kendra %A Krischer, Jeffrey P %A Petrosino, Joseph F %K Adolescent %K Animals %K Bifidobacterium %K Breast Feeding %K Case-Control Studies %K Child %K Child, Preschool %K Cluster Analysis %K Datasets as Topic %K Diabetes Mellitus, Type 1 %K Female %K Firmicutes %K Gastrointestinal Microbiome %K Humans %K Infant %K Male %K Milk, Human %K Pets %K RNA, Ribosomal, 16S %K Siblings %K Surveys and Questionnaires %K Time Factors %X

The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial-immune crosstalk during this time thought to be involved in the pathobiology of later life diseases such as persistent islet autoimmunity and type 1 diabetes. However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children between 3 and 46 months of age by 16S rRNA gene sequencing (n = 12,005) and metagenomic sequencing (n = 10,867), as part of the The Environmental Determinants of Diabetes in the Young (TEDDY) study. We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3-14), a transitional phase (months 15-30), and a stable phase (months 31-46). Receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure. Breastfeeding was associated with higher levels of Bifidobacterium species (B. breve and B. bifidum), and the cessation of breast milk resulted in faster maturation of the gut microbiome, as marked by the phylum Firmicutes. Birth mode was also significantly associated with the microbiome during the developmental phase, driven by higher levels of Bacteroides species (particularly B. fragilis) in infants delivered vaginally. Bacteroides was also associated with increased gut diversity and faster maturation, regardless of the birth mode. Environmental factors including geographical location and household exposures (such as siblings and furry pets) also represented important covariates. A nested case-control analysis revealed subtle associations between microbial taxonomy and the development of islet autoimmunity or type 1 diabetes. These data determine the structural and functional assembly of the microbiome in early life and provide a foundation for targeted mechanistic investigation into the consequences of microbial-immune crosstalk for long-term health.

%B Nature %V 562 %P 583-588 %8 2018 Oct %G eng %N 7728 %1 https://www.ncbi.nlm.nih.gov/pubmed/30356187?dopt=Abstract %R 10.1038/s41586-018-0617-x