%0 Journal Article %J Nat Commun %D 2023 %T Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality. %A Hong, Yun Soo %A Battle, Stephanie L %A Shi, Wen %A Puiu, Daniela %A Pillalamarri, Vamsee %A Xie, Jiaqi %A Pankratz, Nathan %A Lake, Nicole J %A Lek, Monkol %A Rotter, Jerome I %A Rich, Stephen S %A Kooperberg, Charles %A Reiner, Alex P %A Auer, Paul L %A Heard-Costa, Nancy %A Liu, Chunyu %A Lai, Meng %A Murabito, Joanne M %A Levy, Daniel %A Grove, Megan L %A Alonso, Alvaro %A Richard A Gibbs %A Dugan-Perez, Shannon %A Gondek, Lukasz P %A Guallar, Eliseo %A Arking, Dan E %K DNA, Mitochondrial %K Heteroplasmy %K Humans %K Leukemia %K Mitochondria %K Mutation %X

Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint score sum (MSS) and find it associated with all-cause mortality, and with the prevalence and incidence of cancer and cancer-related mortality, particularly leukemia. These results indicate that mitochondria may have a functional role in certain cancers, and mitochondrial heteroplasmic SNVs may serve as a prognostic marker for cancer, especially for leukemia.

%B Nat Commun %V 14 %P 6113 %8 2023 Sep 30 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/37777527?dopt=Abstract %R 10.1038/s41467-023-41785-7 %0 Journal Article %J Diabetes %D 2023 %T Investigating Gene-Diet Interactions Impacting the Association Between Macronutrient Intake and Glycemic Traits. %A Westerman, Kenneth E %A Walker, Maura E %A Gaynor, Sheila M %A Wessel, Jennifer %A DiCorpo, Daniel %A Ma, Jiantao %A Alonso, Alvaro %A Aslibekyan, Stella %A Baldridge, Abigail S %A Bertoni, Alain G %A Biggs, Mary L %A Brody, Jennifer A %A Chen, Yii-Der Ida %A Dupuis, Josée %A Goodarzi, Mark O %A Guo, Xiuqing %A Hasbani, Natalie R %A Heath, Adam %A Hidalgo, Bertha %A Irvin, Marguerite R %A Johnson, W Craig %A Kalyani, Rita R %A Lange, Leslie %A Lemaitre, Rozenn N %A Liu, Ching-Ti %A Liu, Simin %A Moon, Jee-Young %A Nassir, Rami %A Pankow, James S %A Pettinger, Mary %A Raffield, Laura M %A Rasmussen-Torvik, Laura J %A Selvin, Elizabeth %A Senn, Mackenzie K %A Shadyab, Aladdin H %A Smith, Albert V %A Smith, Nicholas L %A Steffen, Lyn %A Talegakwar, Sameera %A Taylor, Kent D %A de Vries, Paul S %A Wilson, James G %A Wood, Alexis C %A Yanek, Lisa R %A Yao, Jie %A Zheng, Yinan %A Eric Boerwinkle %A Morrison, Alanna C %A Fornage, Miriam %A Russell, Tracy P %A Psaty, Bruce M %A Levy, Daniel %A Heard-Costa, Nancy L %A Ramachandran, Vasan S %A Mathias, Rasika A %A Arnett, Donna K %A Kaplan, Robert %A North, Kari E %A Correa, Adolfo %A Carson, April %A Rotter, Jerome I %A Rich, Stephen S %A Manson, JoAnn E %A Reiner, Alexander P %A Kooperberg, Charles %A Florez, Jose C %A Meigs, James B %A Merino, Jordi %A Tobias, Deirdre K %A Chen, Han %A Manning, Alisa K %K Diabetes Mellitus %K Diet %K Eating %K Genome-Wide Association Study %K Glycated Hemoglobin %K Guanine Nucleotide Dissociation Inhibitors %K Humans %X

UNLABELLED: Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate for fat, and its interactions with common and rare variants genome-wide. In main effect meta-analyses, participants consuming more carbohydrate had modestly lower glycemic trait values (e.g., for glycated hemoglobin [HbA1c], -0.013% HbA1c/250 kcal substitution). In GDI meta-analyses, a common African ancestry-enriched variant (rs79762542) reached study-wide significance and replicated in the UK Biobank cohort, indicating a negative carbohydrate-HbA1c association among major allele homozygotes only. Simulations revealed that >150,000 samples may be necessary to identify similar macronutrient GDIs under realistic assumptions about effect size and measurement error. These results generate hypotheses for further exploration of modifiable metabolic disease risk in additional cohorts with African ancestry.

ARTICLE HIGHLIGHTS: We aimed to identify genetic modifiers of the dietary macronutrient-glycemia relationship using whole-genome sequence data from 10 Trans-Omics for Precision Medicine program cohorts. Substitution models indicated a modest reduction in glycemia associated with an increase in dietary carbohydrate at the expense of fat. Genome-wide interaction analysis identified one African ancestry-enriched variant near the FRAS1 gene that may interact with macronutrient intake to influence hemoglobin A1c. Simulation-based power calculations accounting for measurement error suggested that substantially larger sample sizes may be necessary to discover further gene-macronutrient interactions.

%B Diabetes %V 72 %P 653-665 %8 2023 May 01 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/36791419?dopt=Abstract %R 10.2337/db22-0851 %0 Journal Article %J Nat Commun %D 2022 %T Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways. %A Young, William J %A Lahrouchi, Najim %A Isaacs, Aaron %A Duong, ThuyVy %A Foco, Luisa %A Ahmed, Farah %A Brody, Jennifer A %A Salman, Reem %A Noordam, Raymond %A Benjamins, Jan-Walter %A Haessler, Jeffrey %A Lyytikäinen, Leo-Pekka %A Repetto, Linda %A Concas, Maria Pina %A van den Berg, Marten E %A Weiss, Stefan %A Baldassari, Antoine R %A Bartz, Traci M %A Cook, James P %A Evans, Daniel S %A Freudling, Rebecca %A Hines, Oliver %A Isaksen, Jonas L %A Lin, Honghuang %A Mei, Hao %A Moscati, Arden %A Müller-Nurasyid, Martina %A Nursyifa, Casia %A Qian, Yong %A Richmond, Anne %A Roselli, Carolina %A Ryan, Kathleen A %A Tarazona-Santos, Eduardo %A Thériault, Sébastien %A van Duijvenboden, Stefan %A Warren, Helen R %A Yao, Jie %A Raza, Dania %A Aeschbacher, Stefanie %A Ahlberg, Gustav %A Alonso, Alvaro %A Andreasen, Laura %A Bis, Joshua C %A Eric Boerwinkle %A Campbell, Archie %A Catamo, Eulalia %A Cocca, Massimiliano %A Cutler, Michael J %A Darbar, Dawood %A De Grandi, Alessandro %A De Luca, Antonio %A Ding, Jun %A Ellervik, Christina %A Ellinor, Patrick T %A Felix, Stephan B %A Froguel, Philippe %A Fuchsberger, Christian %A Gögele, Martin %A Graff, Claus %A Graff, Mariaelisa %A Guo, Xiuqing %A Hansen, Torben %A Heckbert, Susan R %A Huang, Paul L %A Huikuri, Heikki V %A Hutri-Kähönen, Nina %A Ikram, M Arfan %A Jackson, Rebecca D %A Junttila, Juhani %A Kavousi, Maryam %A Kors, Jan A %A Leal, Thiago P %A Lemaitre, Rozenn N %A Lin, Henry J %A Lind, Lars %A Linneberg, Allan %A Liu, Simin %A Macfarlane, Peter W %A Mangino, Massimo %A Meitinger, Thomas %A Mezzavilla, Massimo %A Mishra, Pashupati P %A Mitchell, Rebecca N %A Mononen, Nina %A Montasser, May E %A Morrison, Alanna C %A Nauck, Matthias %A Nauffal, Victor %A Navarro, Pau %A Nikus, Kjell %A Paré, Guillaume %A Patton, Kristen K %A Pelliccione, Giulia %A Pittman, Alan %A Porteous, David J %A Pramstaller, Peter P %A Preuss, Michael H %A Raitakari, Olli T %A Reiner, Alexander P %A Ribeiro, Antonio Luiz P %A Rice, Kenneth M %A Risch, Lorenz %A Schlessinger, David %A Schotten, Ulrich %A Schurmann, Claudia %A Shen, Xia %A Shoemaker, M Benjamin %A Sinagra, Gianfranco %A Sinner, Moritz F %A Soliman, Elsayed Z %A Stoll, Monika %A Strauch, Konstantin %A Tarasov, Kirill %A Taylor, Kent D %A Tinker, Andrew %A Trompet, Stella %A Uitterlinden, Andre %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Weng, Lu-Chen %A Whitsel, Eric A %A Wilson, James G %A Avery, Christy L %A Conen, David %A Correa, Adolfo %A Cucca, Francesco %A Dörr, Marcus %A Gharib, Sina A %A Girotto, Giorgia %A Grarup, Niels %A Hayward, Caroline %A Jamshidi, Yalda %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Kääb, Stefan %A Kähönen, Mika %A Kanters, Jørgen K %A Kooperberg, Charles %A Lehtimäki, Terho %A Lima-Costa, Maria Fernanda %A Liu, Yongmei %A Loos, Ruth J F %A Lubitz, Steven A %A Mook-Kanamori, Dennis O %A Morris, Andrew P %A O'Connell, Jeffrey R %A Olesen, Morten Salling %A Orini, Michele %A Padmanabhan, Sandosh %A Pattaro, Cristian %A Peters, Annette %A Psaty, Bruce M %A Rotter, Jerome I %A Stricker, Bruno %A van der Harst, Pim %A van Duijn, Cornelia M %A Verweij, Niek %A Wilson, James F %A Arking, Dan E %A Ramirez, Julia %A Lambiase, Pier D %A Sotoodehnia, Nona %A Mifsud, Borbala %A Newton-Cheh, Christopher %A Munroe, Patricia B %K Arrhythmias, Cardiac %K Death, Sudden, Cardiac %K Electrocardiography %K Genetic Testing %K Humans %K Male %X

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

%B Nat Commun %V 13 %P 5144 %8 2022 Sep 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/36050321?dopt=Abstract %R 10.1038/s41467-022-32821-z %0 Journal Article %J Nature %D 2021 %T Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. %A Taliun, Daniel %A Harris, Daniel N %A Kessler, Michael D %A Carlson, Jedidiah %A Szpiech, Zachary A %A Torres, Raul %A Taliun, Sarah A Gagliano %A Corvelo, André %A Gogarten, Stephanie M %A Kang, Hyun Min %A Pitsillides, Achilleas N %A LeFaive, Jonathon %A Lee, Seung-Been %A Tian, Xiaowen %A Browning, Brian L %A Das, Sayantan %A Emde, Anne-Katrin %A Clarke, Wayne E %A Loesch, Douglas P %A Shetty, Amol C %A Blackwell, Thomas W %A Smith, Albert V %A Wong, Quenna %A Liu, Xiaoming %A Conomos, Matthew P %A Bobo, Dean M %A Aguet, Francois %A Albert, Christine %A Alonso, Alvaro %A Ardlie, Kristin G %A Arking, Dan E %A Aslibekyan, Stella %A Auer, Paul L %A Barnard, John %A Barr, R Graham %A Barwick, Lucas %A Becker, Lewis C %A Beer, Rebecca L %A Benjamin, Emelia J %A Bielak, Lawrence F %A Blangero, John %A Boehnke, Michael %A Bowden, Donald W %A Brody, Jennifer A %A Burchard, Esteban G %A Cade, Brian E %A Casella, James F %A Chalazan, Brandon %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Cho, Michael H %A Choi, Seung Hoan %A Chung, Mina K %A Clish, Clary B %A Correa, Adolfo %A Curran, Joanne E %A Custer, Brian %A Darbar, Dawood %A Daya, Michelle %A de Andrade, Mariza %A DeMeo, Dawn L %A Dutcher, Susan K %A Ellinor, Patrick T %A Emery, Leslie S %A Eng, Celeste %A Fatkin, Diane %A Fingerlin, Tasha %A Forer, Lukas %A Fornage, Myriam %A Franceschini, Nora %A Fuchsberger, Christian %A Fullerton, Stephanie M %A Germer, Soren %A Gladwin, Mark T %A Gottlieb, Daniel J %A Guo, Xiuqing %A Hall, Michael E %A He, Jiang %A Heard-Costa, Nancy L %A Heckbert, Susan R %A Irvin, Marguerite R %A Johnsen, Jill M %A Johnson, Andrew D %A Kaplan, Robert %A Kardia, Sharon L R %A Kelly, Tanika %A Kelly, Shannon %A Kenny, Eimear E %A Kiel, Douglas P %A Klemmer, Robert %A Konkle, Barbara A %A Kooperberg, Charles %A Köttgen, Anna %A Lange, Leslie A %A Lasky-Su, Jessica %A Levy, Daniel %A Lin, Xihong %A Lin, Keng-Han %A Liu, Chunyu %A Loos, Ruth J F %A Garman, Lori %A Gerszten, Robert %A Lubitz, Steven A %A Lunetta, Kathryn L %A Mak, Angel C Y %A Manichaikul, Ani %A Manning, Alisa K %A Mathias, Rasika A %A McManus, David D %A McGarvey, Stephen T %A Meigs, James B %A Meyers, Deborah A %A Mikulla, Julie L %A Minear, Mollie A %A Mitchell, Braxton D %A Mohanty, Sanghamitra %A Montasser, May E %A Montgomery, Courtney %A Morrison, Alanna C %A Murabito, Joanne M %A Natale, Andrea %A Natarajan, Pradeep %A Nelson, Sarah C %A North, Kari E %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Pankratz, Nathan %A Peloso, Gina M %A Peyser, Patricia A %A Pleiness, Jacob %A Post, Wendy S %A Psaty, Bruce M %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Roden, Dan %A Rotter, Jerome I %A Ruczinski, Ingo %A Sarnowski, Chloe %A Schoenherr, Sebastian %A Schwartz, David A %A Seo, Jeong-Sun %A Seshadri, Sudha %A Sheehan, Vivien A %A Sheu, Wayne H %A Shoemaker, M Benjamin %A Smith, Nicholas L %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stilp, Adrienne M %A Tang, Weihong %A Taylor, Kent D %A Telen, Marilyn %A Thornton, Timothy A %A Tracy, Russell P %A Van Den Berg, David J %A Vasan, Ramachandran S %A Viaud-Martinez, Karine A %A Vrieze, Scott %A Weeks, Daniel E %A Weir, Bruce S %A Weiss, Scott T %A Weng, Lu-Chen %A Willer, Cristen J %A Zhang, Yingze %A Zhao, Xutong %A Arnett, Donna K %A Ashley-Koch, Allison E %A Barnes, Kathleen C %A Eric Boerwinkle %A Gabriel, Stacey %A Richard A Gibbs %A Rice, Kenneth M %A Rich, Stephen S %A Silverman, Edwin K %A Qasba, Pankaj %A Gan, Weiniu %A Papanicolaou, George J %A Nickerson, Deborah A %A Browning, Sharon R %A Zody, Michael C %A Zöllner, Sebastian %A Wilson, James G %A Cupples, L Adrienne %A Laurie, Cathy C %A Jaquish, Cashell E %A Hernandez, Ryan D %A O'Connor, Timothy D %A Abecasis, Gonçalo R %K Cytochrome P-450 CYP2D6 %K Genetic Variation %K Genome, Human %K Genomics %K Haplotypes %K Heterozygote %K Humans %K INDEL Mutation %K Loss of Function Mutation %K Mutagenesis %K National Heart, Lung, and Blood Institute (U.S.) %K Phenotype %K Polymorphism, Single Nucleotide %K Population Density %K Precision Medicine %K Quality Control %K Sample Size %K United States %K Whole Genome Sequencing %X

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

%B Nature %V 590 %P 290-299 %8 2021 Feb %G eng %N 7845 %1 https://www.ncbi.nlm.nih.gov/pubmed/33568819?dopt=Abstract %R 10.1038/s41586-021-03205-y %0 Journal Article %J eNeurologicalSci %D 2020 %T Corrigendum to 'Association of sickle cell trait with measures of cognitive function and dementia in African Americans' Vol. 16 (2019), 100,201. %A Chen, Nemin %A Caruso, Christina %A Alonso, Alvaro %A Derebail, Vimal K %A Kshirsagar, Abhijit V %A Sharrett, A Richey %A Key, Nigel S %A Gottesman, Rebecca F %A Grove, Megan L %A Bressler, Jan %A Eric Boerwinkle %A Windham, B Gwen %A Mosley, Thomas H %A Hyacinth, Hyacinth I %X

[This corrects the article DOI: 10.1016/j.ensci.2019.100201.].

%B eNeurologicalSci %V 21 %P 100281 %8 2020 Dec %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/33313427?dopt=Abstract %R 10.1016/j.ensci.2020.100281 %0 Journal Article %J eNeurologicalSci %D 2019 %T Association of sickle cell trait with measures of cognitive function and dementia in African Americans. %A Chen, Nemin %A Caruso, Christina %A Alonso, Alvaro %A Derebail, Vimal K %A Kshirsagar, Abhijit V %A Sharrett, A Richey %A Key, Nigel S %A Gottesman, Rebecca F %A Grove, Megan L %A Bressler, Jan %A Eric Boerwinkle %A Windham, B Gwen %A Mosley, Thomas H %A Hyacinth, Hyacinth I %X

OBJECTIVE: The incidence and prevalence of cognitive decline and dementia are significantly higher among African Americans compared with non-Hispanic Whites. The aim of this study was to determine whether inheritance of the sickle cell trait (SCT) i.e. heterozygosity for the sickle cell mutation increases the risk of cognitive decline or dementia Among African Americans.

METHODS: We studied African American participants enrolled in the Atherosclerosis Risk in Communities study. SCT genotype at baseline and outcome data from cognitive assessments at visits 2, 4 and 5, and an MRI performed at visit 5 were analyzed for the association between SCT and risk of cognitive impairment and/or dementia.

RESULTS: There was no significant difference in risk factors profile between participants with SCT ( = 176) and those without SCT ( = 2532). SCT was not independently associated with a higher prevalence of global or domain-specific cognitive impairment at baseline or with more rapid cognitive decline. Participants with SCT had slightly lower incidence of dementia (HR = 0.63 [0.38, 1.05]). On the other hand, SCT seems to interact with the apolipoprotein E ε4 risk allele resulting in poor performance on digit symbol substitution test at baseline (z-score = -0.08, P = 0.05) and over time (z-score = -0.12, P = 0.04); and with diabetes mellitus leading to a moderately increased risk of dementia (HR = 2.06 [0.89, 4.78], P = 0.01).

CONCLUSIONS: SCT was not an independent risk factor for prevalence or incidence of cognitive decline or dementia, although it may interact with and modify other putative risk factors for cognitive decline and dementia.

%B eNeurologicalSci %V 16 %P 100201 %8 2019 Sep %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/31384675?dopt=Abstract %R 10.1016/j.ensci.2019.100201 %0 Journal Article %J J Appl Lab Med %D 2019 %T Reproducibility and Variability of Protein Analytes Measured Using a Multiplexed Modified Aptamer Assay. %A Tin, Adrienne %A Yu, Bing %A Ma, Jianzhong %A Masushita, Kunihiro %A Daya, Natalie %A Hoogeveen, Ron C %A Ballantyne, Christie M %A Couper, David %A Rebholz, Casey M %A Grams, Morgan E %A Alonso, Alvaro %A Mosley, Thomas %A Heiss, Gerardo %A Ganz, Peter %A Selvin, Elizabeth %A Eric Boerwinkle %A Coresh, Josef %K Aged %K Atherosclerosis %K Blood Proteins %K Equipment Design %K Female %K Glomerular Filtration Rate %K Humans %K Male %K Middle Aged %K Prospective Studies %K Proteomics %K Reproducibility of Results %X

BACKGROUND: There is growing interest in the use of multiplexed aptamer-based assays for large-scale proteomic studies. However, the analytic, short- and long-term variation of the measured proteins is largely uncharacterized.

METHODS: We quantified 4001 plasma protein analytes from 42 participants in the Atherosclerosis Risk in Communities (ARIC) Study in split samples and at multiple visits using a multiplexed modified aptamer assay. We calculated the CV, Spearman correlation, and intraclass correlation (ICC) between split samples and evaluated the short-term (4-9 weeks) and long-term (approximately 20 years) variability using paired -tests with log-transformed protein concentrations and Bonferroni-corrected significance thresholds. We performed principal component (PC) analysis of protein analyte concentrations and evaluated their associations with age, sex, race, and estimated glomerular filtration rate (eGFR).

RESULTS: The mean baseline age was 57 years at the first visit, 43% of participants were male and 57% were white. Among 3693 protein analytes that passed quality control, half (n = 1846) had CVs < 5.0%, Spearman correlations > 0.89, and ICCs > 0.96 among the split samples. Over the short term, only 1 analyte had a statistically significant difference between the 2 time points, whereas, over approximately 20 years, 866 analytes (23.4%) had statistically significant differences ( < 1.4 × 10, 681 increased, 185 decreased). PC1 had high correlations with age (-0.73) and eGFR (0.60). PC2 had moderate correlation with male sex (0.18) and white race (0.31).

CONCLUSIONS: Multiplexed modified aptamer technology can assay thousands of proteins with excellent precision. Our results support the potential for large-scale studies of the plasma proteome over the lifespan.

%B J Appl Lab Med %V 4 %P 30-39 %8 2019 Jul %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31639705?dopt=Abstract %R 10.1373/jalm.2018.027086 %0 Journal Article %J Circ Genom Precis Med %D 2018 %T Common Coding Variants in Are Associated With the Nav1.8 Late Current and Cardiac Conduction. %A Macri, Vincenzo %A Brody, Jennifer A %A Arking, Dan E %A Hucker, William J %A Yin, Xiaoyan %A Lin, Honghuang %A Mills, Robert W %A Sinner, Moritz F %A Lubitz, Steven A %A Liu, Ching-Ti %A Morrison, Alanna C %A Alonso, Alvaro %A Li, Ning %A Fedorov, Vadim V %A Janssen, Paul M %A Bis, Joshua C %A Heckbert, Susan R %A Dolmatova, Elena V %A Lumley, Thomas %A Sitlani, Colleen M %A Cupples, L Adrienne %A Pulit, Sara L %A Newton-Cheh, Christopher %A Barnard, John %A Smith, Jonathan D %A Van Wagoner, David R %A Chung, Mina K %A Vlahakes, Gus J %A O'Donnell, Christopher J %A Rotter, Jerome I %A Margulies, Kenneth B %A Morley, Michael P %A Cappola, Thomas P %A Benjamin, Emelia J %A Muzny, Donna %A Gibbs, Richard A %A Jackson, Rebecca D %A Magnani, Jared W %A Herndon, Caroline N %A Rich, Stephen S %A Psaty, Bruce M %A Milan, David J %A Boerwinkle, Eric %A Mohler, Peter J %A Sotoodehnia, Nona %A Ellinor, Patrick T %K Biophysical Phenomena %K Electrocardiography %K Genetic Association Studies %K Haplotypes %K Heart Conduction System %K Humans %K Ion Channel Gating %K Mutation, Missense %K NAV1.8 Voltage-Gated Sodium Channel %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

BACKGROUND: Genetic variants at the / locus are strongly associated with electrocardiographic PR and QRS intervals. While is the canonical cardiac sodium channel gene, the role of in cardiac conduction is less well characterized.

METHODS: We sequenced the locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology.

RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium (  =0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, =1.52×10) and QRS intervals (rs6599251, QRS β=-0.73; =1.2×10), respectively. Although these variants were not associated with or expression in human atrial tissue (n=490), they were in high linkage disequilibrium (  ≥0.72) with a common missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, =0.03, and I962V+V1073A, 22.4±0.8%, =0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, =0.03).

CONCLUSIONS: Our findings suggest an association between genetic variation in , the late sodium current, and alterations in cardiac conduction.

%B Circ Genom Precis Med %V 11 %P e001663 %8 2018 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/29752399?dopt=Abstract %R 10.1161/CIRCGEN.116.001663 %0 Journal Article %J Nat Genet %D 2018 %T Multi-ethnic genome-wide association study for atrial fibrillation. %A Roselli, Carolina %A Chaffin, Mark D %A Weng, Lu-Chen %A Aeschbacher, Stefanie %A Ahlberg, Gustav %A Albert, Christine M %A Almgren, Peter %A Alonso, Alvaro %A Anderson, Christopher D %A Aragam, Krishna G %A Arking, Dan E %A Barnard, John %A Bartz, Traci M %A Benjamin, Emelia J %A Bihlmeyer, Nathan A %A Bis, Joshua C %A Bloom, Heather L %A Boerwinkle, Eric %A Bottinger, Erwin B %A Brody, Jennifer A %A Calkins, Hugh %A Campbell, Archie %A Cappola, Thomas P %A Carlquist, John %A Chasman, Daniel I %A Chen, Lin Y %A Chen, Yii-Der Ida %A Choi, Eue-Keun %A Choi, Seung Hoan %A Christophersen, Ingrid E %A Chung, Mina K %A Cole, John W %A Conen, David %A Cook, James %A Crijns, Harry J %A Cutler, Michael J %A Damrauer, Scott M %A Daniels, Brian R %A Darbar, Dawood %A Delgado, Graciela %A Denny, Joshua C %A Dichgans, Martin %A Dörr, Marcus %A Dudink, Elton A %A Dudley, Samuel C %A Esa, Nada %A Esko, Tõnu %A Eskola, Markku %A Fatkin, Diane %A Felix, Stephan B %A Ford, Ian %A Franco, Oscar H %A Geelhoed, Bastiaan %A Grewal, Raji P %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gupta, Namrata %A Gustafsson, Stefan %A Gutmann, Rebecca %A Hamsten, Anders %A Harris, Tamara B %A Hayward, Caroline %A Heckbert, Susan R %A Hernesniemi, Jussi %A Hocking, Lynne J %A Hofman, Albert %A Horimoto, Andrea R V R %A Huang, Jie %A Huang, Paul L %A Huffman, Jennifer %A Ingelsson, Erik %A Ipek, Esra Gucuk %A Ito, Kaoru %A Jimenez-Conde, Jordi %A Johnson, Renee %A Jukema, J Wouter %A Kääb, Stefan %A Kähönen, Mika %A Kamatani, Yoichiro %A Kane, John P %A Kastrati, Adnan %A Kathiresan, Sekar %A Katschnig-Winter, Petra %A Kavousi, Maryam %A Kessler, Thorsten %A Kietselaer, Bas L %A Kirchhof, Paulus %A Kleber, Marcus E %A Knight, Stacey %A Krieger, Jose E %A Kubo, Michiaki %A Launer, Lenore J %A Laurikka, Jari %A Lehtimäki, Terho %A Leineweber, Kirsten %A Lemaitre, Rozenn N %A Li, Man %A Lim, Hong Euy %A Lin, Henry J %A Lin, Honghuang %A Lind, Lars %A Lindgren, Cecilia M %A Lokki, Marja-Liisa %A London, Barry %A Loos, Ruth J F %A Low, Siew-Kee %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Macfarlane, Peter W %A Magnusson, Patrik K %A Mahajan, Anubha %A Malik, Rainer %A Mansur, Alfredo J %A Marcus, Gregory M %A Margolin, Lauren %A Margulies, Kenneth B %A Marz, Winfried %A McManus, David D %A Melander, Olle %A Mohanty, Sanghamitra %A Montgomery, Jay A %A Morley, Michael P %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Natale, Andrea %A Nazarian, Saman %A Neumann, Benjamin %A Newton-Cheh, Christopher %A Niemeijer, Maartje N %A Nikus, Kjell %A Nilsson, Peter %A Noordam, Raymond %A Oellers, Heidi %A Olesen, Morten S %A Orho-Melander, Marju %A Padmanabhan, Sandosh %A Pak, Hui-Nam %A Paré, Guillaume %A Pedersen, Nancy L %A Pera, Joanna %A Pereira, Alexandre %A Porteous, David %A Psaty, Bruce M %A Pulit, Sara L %A Pullinger, Clive R %A Rader, Daniel J %A Refsgaard, Lena %A Ribasés, Marta %A Ridker, Paul M %A Rienstra, Michiel %A Risch, Lorenz %A Roden, Dan M %A Rosand, Jonathan %A Rosenberg, Michael A %A Rost, Natalia %A Rotter, Jerome I %A Saba, Samir %A Sandhu, Roopinder K %A Schnabel, Renate B %A Schramm, Katharina %A Schunkert, Heribert %A Schurman, Claudia %A Scott, Stuart A %A Seppälä, Ilkka %A Shaffer, Christian %A Shah, Svati %A Shalaby, Alaa A %A Shim, Jaemin %A Shoemaker, M Benjamin %A Siland, Joylene E %A Sinisalo, Juha %A Sinner, Moritz F %A Slowik, Agnieszka %A Smith, Albert V %A Smith, Blair H %A Smith, J Gustav %A Smith, Jonathan D %A Smith, Nicholas L %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Stricker, Bruno H %A Sun, Albert %A Sun, Han %A Svendsen, Jesper H %A Tanaka, Toshihiro %A Tanriverdi, Kahraman %A Taylor, Kent D %A Teder-Laving, Maris %A Teumer, Alexander %A Thériault, Sébastien %A Trompet, Stella %A Tucker, Nathan R %A Tveit, Arnljot %A Uitterlinden, André G %A van der Harst, Pim %A Van Gelder, Isabelle C %A Van Wagoner, David R %A Verweij, Niek %A Vlachopoulou, Efthymia %A Völker, Uwe %A Wang, Biqi %A Weeke, Peter E %A Weijs, Bob %A Weiss, Raul %A Weiss, Stefan %A Wells, Quinn S %A Wiggins, Kerri L %A Wong, Jorge A %A Woo, Daniel %A Worrall, Bradford B %A Yang, Pil-Sung %A Yao, Jie %A Yoneda, Zachary T %A Zeller, Tanja %A Zeng, Lingyao %A Lubitz, Steven A %A Lunetta, Kathryn L %A Ellinor, Patrick T %K Atrial Fibrillation %K Case-Control Studies %K Ethnicity %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Quantitative Trait Loci %K Transcriptome %X

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

%B Nat Genet %V 50 %P 1225-1233 %8 2018 Jun 11 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/29892015?dopt=Abstract %R 10.1038/s41588-018-0133-9 %0 Journal Article %J Nat Genet %D 2017 %T Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. %A Christophersen, Ingrid E %A Rienstra, Michiel %A Roselli, Carolina %A Yin, Xiaoyan %A Geelhoed, Bastiaan %A Barnard, John %A Lin, Honghuang %A Arking, Dan E %A Smith, Albert V %A Albert, Christine M %A Chaffin, Mark %A Tucker, Nathan R %A Li, Molong %A Klarin, Derek %A Bihlmeyer, Nathan A %A Low, Siew-Kee %A Weeke, Peter E %A Müller-Nurasyid, Martina %A Smith, J Gustav %A Brody, Jennifer A %A Niemeijer, Maartje N %A Dörr, Marcus %A Trompet, Stella %A Huffman, Jennifer %A Gustafsson, Stefan %A Schurmann, Claudia %A Kleber, Marcus E %A Lyytikäinen, Leo-Pekka %A Seppälä, Ilkka %A Malik, Rainer %A Horimoto, Andrea R V R %A Perez, Marco %A Sinisalo, Juha %A Aeschbacher, Stefanie %A Thériault, Sébastien %A Yao, Jie %A Radmanesh, Farid %A Weiss, Stefan %A Teumer, Alexander %A Choi, Seung Hoan %A Weng, Lu-Chen %A Clauss, Sebastian %A Deo, Rajat %A Rader, Daniel J %A Shah, Svati H %A Sun, Albert %A Hopewell, Jemma C %A Debette, Stephanie %A Chauhan, Ganesh %A Yang, Qiong %A Worrall, Bradford B %A Paré, Guillaume %A Kamatani, Yoichiro %A Hagemeijer, Yanick P %A Verweij, Niek %A Siland, Joylene E %A Kubo, Michiaki %A Smith, Jonathan D %A Van Wagoner, David R %A Bis, Joshua C %A Perz, Siegfried %A Psaty, Bruce M %A Ridker, Paul M %A Magnani, Jared W %A Harris, Tamara B %A Launer, Lenore J %A Shoemaker, M Benjamin %A Padmanabhan, Sandosh %A Haessler, Jeffrey %A Bartz, Traci M %A Waldenberger, Melanie %A Lichtner, Peter %A Arendt, Marina %A Krieger, Jose E %A Kähönen, Mika %A Risch, Lorenz %A Mansur, Alfredo J %A Peters, Annette %A Smith, Blair H %A Lind, Lars %A Scott, Stuart A %A Lu, Yingchang %A Bottinger, Erwin B %A Hernesniemi, Jussi %A Lindgren, Cecilia M %A Wong, Jorge A %A Huang, Jie %A Eskola, Markku %A Morris, Andrew P %A Ford, Ian %A Reiner, Alex P %A Delgado, Graciela %A Chen, Lin Y %A Chen, Yii-Der Ida %A Sandhu, Roopinder K %A Li, Man %A Boerwinkle, Eric %A Eisele, Lewin %A Lannfelt, Lars %A Rost, Natalia %A Anderson, Christopher D %A Taylor, Kent D %A Campbell, Archie %A Magnusson, Patrik K %A Porteous, David %A Hocking, Lynne J %A Vlachopoulou, Efthymia %A Pedersen, Nancy L %A Nikus, Kjell %A Orho-Melander, Marju %A Hamsten, Anders %A Heeringa, Jan %A Denny, Joshua C %A Kriebel, Jennifer %A Darbar, Dawood %A Newton-Cheh, Christopher %A Shaffer, Christian %A Macfarlane, Peter W %A Heilmann-Heimbach, Stefanie %A Almgren, Peter %A Huang, Paul L %A Sotoodehnia, Nona %A Soliman, Elsayed Z %A Uitterlinden, André G %A Hofman, Albert %A Franco, Oscar H %A Völker, Uwe %A Jöckel, Karl-Heinz %A Sinner, Moritz F %A Lin, Henry J %A Guo, Xiuqing %A Dichgans, Martin %A Ingelsson, Erik %A Kooperberg, Charles %A Melander, Olle %A Loos, Ruth J F %A Laurikka, Jari %A Conen, David %A Rosand, Jonathan %A van der Harst, Pim %A Lokki, Marja-Liisa %A Kathiresan, Sekar %A Pereira, Alexandre %A Jukema, J Wouter %A Hayward, Caroline %A Rotter, Jerome I %A Marz, Winfried %A Lehtimäki, Terho %A Stricker, Bruno H %A Chung, Mina K %A Felix, Stephan B %A Gudnason, Vilmundur %A Alonso, Alvaro %A Roden, Dan M %A Kääb, Stefan %A Chasman, Daniel I %A Heckbert, Susan R %A Benjamin, Emelia J %A Tanaka, Toshihiro %A Lunetta, Kathryn L %A Lubitz, Steven A %A Ellinor, Patrick T %K Atrial Fibrillation %K Black or African American %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Quantitative Trait Loci %K White People %X

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

%B Nat Genet %V 49 %P 946-952 %8 2017 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/28416818?dopt=Abstract %R 10.1038/ng.3843 %0 Journal Article %J PLoS Genet %D 2016 %T Whole Exome Sequencing in Atrial Fibrillation. %A Lubitz, Steven A %A Brody, Jennifer A %A Bihlmeyer, Nathan A %A Roselli, Carolina %A Weng, Lu-Chen %A Christophersen, Ingrid E %A Alonso, Alvaro %A Boerwinkle, Eric %A Gibbs, Richard A %A Bis, Joshua C %A Cupples, L Adrienne %A Mohler, Peter J %A Nickerson, Deborah A %A Muzny, Donna %A Perez, Marco V %A Psaty, Bruce M %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Lunetta, Kathryn L %A Benjamin, Emelia J %A Heckbert, Susan R %A Arking, Dan E %A Ellinor, Patrick T %A Lin, Honghuang %K Aged %K Atrial Fibrillation %K Exome %K Female %K Gene Frequency %K Genetic Association Studies %K Genetic Predisposition to Disease %K High-Throughput Nucleotide Sequencing %K Humans %K Male %K Microfilament Proteins %K Middle Aged %K Polymorphism, Single Nucleotide %X

Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.

%B PLoS Genet %V 12 %P e1006284 %8 2016 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/27589061?dopt=Abstract %R 10.1371/journal.pgen.1006284 %0 Journal Article %J PLoS One %D 2015 %T Metabolomics and Incidence of Atrial Fibrillation in African Americans: The Atherosclerosis Risk in Communities (ARIC) Study. %A Alonso, Alvaro %A Yu, Bing %A Qureshi, Waqas T %A Grams, Morgan E %A Selvin, Elizabeth %A Soliman, Elsayed Z %A Loehr, Laura R %A Chen, Lin Y %A Agarwal, Sunil K %A Alexander, Danny %A Boerwinkle, Eric %K Atherosclerosis %K Atrial Fibrillation %K Black or African American %K Female %K Humans %K Incidence %K Male %K Metabolomics %K Middle Aged %K Residence Characteristics %X

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia. Application of metabolomic approaches, which may identify novel pathways and biomarkers of disease risk, to a longitudinal epidemiologic study of AF has been limited.

METHODS: We determined the prospective association of 118 serum metabolites identified through untargeted metabolomics profiling with the incidence of newly-diagnosed AF in 1919 African-American men and women from the Atherosclerosis Risk in Communities study without AF at baseline (1987-1989). Incident AF cases through 2011 were ascertained from study electrocardiograms, hospital discharge codes, and death certificates.

RESULTS: During a median follow-up of 22 years, we identified 183 incident AF cases. In Cox proportional hazards models adjusted for age, sex, smoking, body mass index, systolic blood pressure, use of antihypertensive medication, diabetes, prevalent heart failure, prevalent coronary heart disease, and kidney function, two conjugated bile acids (glycolithocholate sulfate and glycocholenate sulfate) were significantly associated with AF risk after correcting for multiple comparisons (p<0.0004). Multivariable-adjusted hazard ratios (95% confidence intervals) of AF were 1.22 (1.12-1.32) for glycolithocholate sulfate and 1.22 (1.10-1.35) for glycocholenate sulfate per 1-standard deviation higher levels. Associations were not appreciably different after additional adjustment for alcohol consumption or concentrations of circulating albumin and liver enzymes.

CONCLUSION: We found an association of higher levels of two bile acids with an increased risk of AF, pointing to a potential novel pathway in AF pathogenesis. Replication of results in independent studies is warranted.

%B PLoS One %V 10 %P e0142610 %8 2015 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/26544570?dopt=Abstract %R 10.1371/journal.pone.0142610 %0 Journal Article %J Heart Rhythm %D 2014 %T Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study. %A Lin, Honghuang %A Sinner, Moritz F %A Brody, Jennifer A %A Arking, Dan E %A Lunetta, Kathryn L %A Rienstra, Michiel %A Lubitz, Steven A %A Magnani, Jared W %A Sotoodehnia, Nona %A McKnight, Barbara %A McManus, David D %A Boerwinkle, Eric %A Psaty, Bruce M %A Rotter, Jerome I %A Bis, Joshua C %A Gibbs, Richard A %A Muzny, Donna %A Kovar, Christie L %A Morrison, Alanna C %A Gupta, Mayetri %A Folsom, Aaron R %A Kääb, Stefan %A Heckbert, Susan R %A Alonso, Alvaro %A Ellinor, Patrick T %A Benjamin, Emelia J %K Aged %K Atrial Fibrillation %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Homeodomain Proteins %K Humans %K Linkage Disequilibrium %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Interleukin-6 %X

BACKGROUND: Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.

OBJECTIVE: To study the association of genetic variants with AF at GWAS top loci.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.

RESULTS: One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).

CONCLUSIONS: We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.

%B Heart Rhythm %V 11 %P 452-7 %8 2014 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/24239840?dopt=Abstract %R 10.1016/j.hrthm.2013.11.012 %0 Journal Article %J Genet Epidemiol %D 2013 %T Genome-wide association study of a heart failure related metabolomic profile among African Americans in the Atherosclerosis Risk in Communities (ARIC) study. %A Yu, Bing %A Zheng, Yan %A Alexander, Danny %A Manolio, Teri A %A Alonso, Alvaro %A Nettleton, Jennifer A %A Boerwinkle, Eric %K Acetyltransferases %K Alleles %K Atherosclerosis %K Black or African American %K Chromosomes, Human, Pair 2 %K Chromosomes, Human, Pair 5 %K Cohort Studies %K Fatty Acids, Unsaturated %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heart Failure %K Humans %K Incidence %K Isoleucine %K Leucine %K Male %K Metabolome %K Metabolomics %K Middle Aged %K Polymorphism, Single Nucleotide %K Pyrrolidonecarboxylic Acid %K Risk Factors %X

Both the prevalence and incidence of heart failure (HF) are increasing, especially among African Americans, but no large-scale, genome-wide association study (GWAS) of HF-related metabolites has been reported. We sought to identify novel genetic variants that are associated with metabolites previously reported to relate to HF incidence. GWASs of three metabolites identified previously as risk factors for incident HF (pyroglutamine, dihydroxy docosatrienoic acid, and X-11787, being either hydroxy-leucine or hydroxy-isoleucine) were performed in 1,260 African Americans free of HF at the baseline examination of the Atherosclerosis Risk in Communities (ARIC) study. A significant association on chromosome 5q33 (rs10463316, MAF = 0.358, P-value = 1.92 × 10(-10) ) was identified for pyroglutamine. One region on chromosome 2p13 contained a nonsynonymous substitution in N-acetyltransferase 8 (NAT8) was associated with X-11787 (rs13538, MAF = 0.481, P-value = 1.71 × 10(-23) ). The smallest P-value for dihydroxy docosatrienoic acid was rs4006531 on chromosome 8q24 (MAF = 0.400, P-value = 6.98 × 10(-7) ). None of the above SNPs were individually associated with incident HF, but a genetic risk score (GRS) created by summing the most significant risk alleles from each metabolite detected 11% greater risk of HF per allele. In summary, we identified three loci associated with previously reported HF-related metabolites. Further use of metabolomics technology will facilitate replication of these findings in independent samples.

%B Genet Epidemiol %V 37 %P 840-5 %8 2013 Dec %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/23934736?dopt=Abstract %R 10.1002/gepi.21752