%0 Journal Article %J Genetics %D 2023 %T Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants. %A Einson, Jonah %A Glinos, Dafni %A Eric Boerwinkle %A Castaldi, Peter %A Darbar, Dawood %A de Andrade, Mariza %A Ellinor, Patrick %A Fornage, Myriam %A Gabriel, Stacey %A Germer, Soren %A Richard A Gibbs %A Hersh, Craig P %A Johnsen, Jill %A Kaplan, Robert %A Konkle, Barbara A %A Kooperberg, Charles %A Nassir, Rami %A Loos, Ruth J F %A Meyers, Deborah A %A Mitchell, Braxton D %A Psaty, Bruce %A Vasan, Ramachandran S %A Rich, Stephen S %A Rienstra, Michael %A Rotter, Jerome I %A Saferali, Aabida %A Shoemaker, Moore Benjamin %A Silverman, Edwin %A Smith, Albert Vernon %A Mohammadi, Pejman %A Castel, Stephane E %A Iossifov, Ivan %A Lappalainen, Tuuli %K Alternative Splicing %K Exons %K Genotype %K Penetrance %K RNA Splice Sites %K RNA Splicing %K RNA, Messenger %X

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

%B Genetics %V 224 %8 2023 Aug 09 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/37348055?dopt=Abstract %R 10.1093/genetics/iyad115 %0 Journal Article %J bioRxiv %D 2023 %T Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants. %A Einson, Jonah %A Glinos, Dafni %A Eric Boerwinkle %A Castaldi, Peter %A Darbar, Dawood %A de Andrade, Mariza %A Ellinor, Patrick %A Fornage, Myriam %A Gabriel, Stacey %A Germer, Soren %A Richard A Gibbs %A Hersh, Craig P %A Johnsen, Jill %A Kaplan, Robert %A Konkle, Barbara A %A Kooperberg, Charles %A Nassir, Rami %A Loos, Ruth J F %A Meyers, Deborah A %A Mitchell, Braxton D %A Psaty, Bruce %A Vasan, Ramachandran S %A Rich, Stephen S %A Rienstra, Michael %A Rotter, Jerome I %A Saferali, Aabida %A Shoemaker, M Benjamin %A Silverman, Edwin %A Smith, Albert Vernon %A Mohammadi, Pejman %A Castel, Stephane E %A Iossifov, Ivan %A Lappalainen, Tuuli %X

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-seq data in GTEx v8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased WGS data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

%B bioRxiv %8 2023 Jan 31 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/36778406?dopt=Abstract %R 10.1101/2023.01.31.526505 %0 Journal Article %J PLoS One %D 2020 %T Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. %A Hahn, Julie %A Fu, Yi-Ping %A Brown, Michael R %A Bis, Joshua C %A de Vries, Paul S %A Feitosa, Mary F %A Yanek, Lisa R %A Weiss, Stefan %A Giulianini, Franco %A Smith, Albert Vernon %A Guo, Xiuqing %A Bartz, Traci M %A Becker, Diane M %A Becker, Lewis C %A Eric Boerwinkle %A Brody, Jennifer A %A Chen, Yii-Der Ida %A Franco, Oscar H %A Grove, Megan %A Harris, Tamara B %A Hofman, Albert %A Hwang, Shih-Jen %A Kral, Brian G %A Launer, Lenore J %A Markus, Marcello R P %A Rice, Kenneth M %A Rich, Stephen S %A Ridker, Paul M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Sotoodehnia, Nona %A Taylor, Kent D %A Uitterlinden, André G %A Völker, Uwe %A Völzke, Henry %A Yao, Jie %A Chasman, Daniel I %A Dörr, Marcus %A Gudnason, Vilmundur %A Mathias, Rasika A %A Post, Wendy %A Psaty, Bruce M %A Dehghan, Abbas %A O'Donnell, Christopher J %A Morrison, Alanna C %K Aging %K Coronary Artery Disease %K Cross-Sectional Studies %K Europe %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %K White People %X

BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

%B PLoS One %V 15 %P e0230035 %8 2020 %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/33186364?dopt=Abstract %R 10.1371/journal.pone.0230035 %0 Journal Article %J Hum Mol Genet %D 2019 %T A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure. %A Sung, Yun Ju %A de Las Fuentes, Lisa %A Winkler, Thomas W %A Chasman, Daniel I %A Bentley, Amy R %A Kraja, Aldi T %A Ntalla, Ioanna %A Warren, Helen R %A Guo, Xiuqing %A Schwander, Karen %A Manning, Alisa K %A Brown, Michael R %A Aschard, Hugues %A Feitosa, Mary F %A Franceschini, Nora %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Kilpeläinen, Tuomas O %A Richard, Melissa A %A Aslibekyan, Stella %A Bartz, Traci M %A Dorajoo, Rajkumar %A Li, Changwei %A Liu, Yongmei %A Rankinen, Tuomo %A Smith, Albert Vernon %A Tajuddin, Salman M %A Tayo, Bamidele O %A Zhao, Wei %A Zhou, Yanhua %A Matoba, Nana %A Sofer, Tamar %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Giulianini, Franco %A Goel, Anuj %A Harris, Sarah E %A Hartwig, Fernando P %A He, Meian %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kammerer, Candace M %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kühnel, Brigitte %A Leander, Karin %A Lee, Wen-Jane %A Lin, Keng-Hung %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A McKenzie, Colin A %A Nelson, Christopher P %A Noordam, Raymond %A Scott, Robert A %A Sheu, Wayne H H %A Stančáková, Alena %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Waken, Robert J %A Wang, Heming %A Wang, Yajuan %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Alfred, Tamuno %A Amin, Najaf %A Arking, Dan E %A Aung, Tin %A Barr, R Graham %A Bielak, Lawrence F %A Eric Boerwinkle %A Bottinger, Erwin P %A Braund, Peter S %A Brody, Jennifer A %A Broeckel, Ulrich %A Cade, Brian %A Campbell, Archie %A Canouil, Mickaël %A Chakravarti, Aravinda %A Cocca, Massimiliano %A Collins, Francis S %A Connell, John M %A de Mutsert, Renée %A de Silva, H Janaka %A Dörr, Marcus %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Evangelou, Evangelos %A Faul, Jessica D %A Forouhi, Nita G %A Franco, Oscar H %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Gu, C Charles %A Gupta, Preeti %A Hagenaars, Saskia P %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hofman, Albert %A Howard, Barbara V %A Hunt, Steven C %A Irvin, Marguerite R %A Jia, Yucheng %A Katsuya, Tomohiro %A Kaufman, Joel %A Kerrison, Nicola D %A Khor, Chiea Chuen %A Koh, Woon-Puay %A Koistinen, Heikki A %A Kooperberg, Charles B %A Krieger, Jose E %A Kubo, Michiaki %A Kutalik, Zoltán %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Joseph H %A Lehne, Benjamin %A Levy, Daniel %A Lewis, Cora E %A Li, Yize %A Lim, Sing Hui %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Jingmin %A Liu, Yeheng %A Loh, Marie %A Lohman, Kurt K %A Louie, Tin %A Mägi, Reedik %A Matsuda, Koichi %A Meitinger, Thomas %A Metspalu, Andres %A Milani, Lili %A Momozawa, Yukihide %A Mosley, Thomas H %A Nalls, Mike A %A Nasri, Ubaydah %A O'Connell, Jeff R %A Ogunniyi, Adesola %A Palmas, Walter R %A Palmer, Nicholette D %A Pankow, James S %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Porteous, David %A Raitakari, Olli T %A Renstrom, Frida %A Rice, Treva K %A Ridker, Paul M %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Sandow, Kevin %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Sever, Peter %A Sims, Mario %A Sitlani, Colleen M %A Smith, Blair H %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya Xing %A Wei, Wen Bin %A Wilson, Gregory %A Wojczynski, Mary K %A Xiang, Yong-Bing %A Yao, Jie %A Yuan, Jian-Min %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Chen, Yii-Der Ida %A Weir, David R %A de Faire, Ulf %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Forrester, Terrence %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo Lessa %A Hung, Yi-Jen %A Jonas, Jost Bruno %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Lehtimäki, Terho %A Liang, Kae-Woei %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Pereira, Alexandre C %A Perls, Thomas %A Rauramaa, Rainer %A Redline, Susan %A Rettig, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Kamatani, Yoichiro %A Laurie, Cathy C %A Bouchard, Claude %A Cooper, Richard S %A Evans, Michele K %A Gudnason, Vilmundur %A Hixson, James %A Kardia, Sharon L R %A Kritchevsky, Stephen B %A Psaty, Bruce M %A van Dam, Rob M %A Arnett, Donna K %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Reiner, Alex P %A Rotimi, Charles N %A Bierut, Laura J %A Zhu, Xiaofeng %A Cupples, L Adrienne %A Province, Michael A %A Rotter, Jerome I %A Franks, Paul W %A Rice, Kenneth %A Elliott, Paul %A Caulfield, Mark J %A Gauderman, W James %A Munroe, Patricia B %A Rao, Dabeeru C %A Morrison, Alanna C %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Antiporters %K Arterial Pressure %K Blood Pressure %K Caspase 9 %K Ethnicity %K Female %K Gene-Environment Interaction %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Membrane Proteins %K Middle Aged %K Polymorphism, Genetic %K Racial Groups %K Receptors, Vasopressin %K Smoking %K Sulfate Transporters %K Tumor Suppressor Proteins %K Young Adult %X

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

%B Hum Mol Genet %V 28 %P 2615-2633 %8 2019 Aug 01 %G eng %N 15 %1 https://www.ncbi.nlm.nih.gov/pubmed/31127295?dopt=Abstract %R 10.1093/hmg/ddz070 %0 Journal Article %J Nat Genet %D 2018 %T Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. %A Mahajan, Anubha %A Wessel, Jennifer %A Willems, Sara M %A Zhao, Wei %A Robertson, Neil R %A Chu, Audrey Y %A Gan, Wei %A Kitajima, Hidetoshi %A Taliun, Daniel %A Rayner, N William %A Guo, Xiuqing %A Lu, Yingchang %A Li, Man %A Jensen, Richard A %A Hu, Yao %A Huo, Shaofeng %A Lohman, Kurt K %A Zhang, Weihua %A Cook, James P %A Prins, Bram Peter %A Flannick, Jason %A Grarup, Niels %A Trubetskoy, Vassily Vladimirovich %A Kravic, Jasmina %A Kim, Young Jin %A Rybin, Denis V %A Yaghootkar, Hanieh %A Müller-Nurasyid, Martina %A Meidtner, Karina %A Li-Gao, Ruifang %A Varga, Tibor V %A Marten, Jonathan %A Li, Jin %A Smith, Albert Vernon %A An, Ping %A Ligthart, Symen %A Gustafsson, Stefan %A Malerba, Giovanni %A Demirkan, Ayse %A Tajes, Juan Fernandez %A Steinthorsdottir, Valgerdur %A Wuttke, Matthias %A Lecoeur, Cécile %A Preuss, Michael %A Bielak, Lawrence F %A Graff, Marielisa %A Highland, Heather M %A Justice, Anne E %A Liu, Dajiang J %A Marouli, Eirini %A Peloso, Gina Marie %A Warren, Helen R %A Afaq, Saima %A Afzal, Shoaib %A Ahlqvist, Emma %A Almgren, Peter %A Amin, Najaf %A Bang, Lia B %A Bertoni, Alain G %A Bombieri, Cristina %A Bork-Jensen, Jette %A Brandslund, Ivan %A Brody, Jennifer A %A Burtt, Noël P %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Cho, Yoon Shin %A Christensen, Cramer %A Eastwood, Sophie V %A Eckardt, Kai-Uwe %A Fischer, Krista %A Gambaro, Giovanni %A Giedraitis, Vilmantas %A Grove, Megan L %A de Haan, Hugoline G %A Hackinger, Sophie %A Hai, Yang %A Han, Sohee %A Tybjærg-Hansen, Anne %A Hivert, Marie-France %A Isomaa, Bo %A Jäger, Susanne %A Jørgensen, Marit E %A Jørgensen, Torben %A Käräjämäki, Annemari %A Kim, Bong-Jo %A Kim, Sung Soo %A Koistinen, Heikki A %A Kovacs, Peter %A Kriebel, Jennifer %A Kronenberg, Florian %A Läll, Kristi %A Lange, Leslie A %A Lee, Jung-Jin %A Lehne, Benjamin %A Li, Huaixing %A Lin, Keng-Hung %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jun %A Loh, Marie %A Mägi, Reedik %A Mamakou, Vasiliki %A McKean-Cowdin, Roberta %A Nadkarni, Girish %A Neville, Matt %A Nielsen, Sune F %A Ntalla, Ioanna %A Peyser, Patricia A %A Rathmann, Wolfgang %A Rice, Kenneth %A Rich, Stephen S %A Rode, Line %A Rolandsson, Olov %A Schönherr, Sebastian %A Selvin, Elizabeth %A Small, Kerrin S %A Stančáková, Alena %A Surendran, Praveen %A Taylor, Kent D %A Teslovich, Tanya M %A Thorand, Barbara %A Thorleifsson, Gudmar %A Tin, Adrienne %A Tonjes, Anke %A Varbo, Anette %A Witte, Daniel R %A Wood, Andrew R %A Yajnik, Pranav %A Yao, Jie %A Yengo, Loic %A Young, Robin %A Amouyel, Philippe %A Boeing, Heiner %A Boerwinkle, Eric %A Bottinger, Erwin P %A Chowdhury, Rajiv %A Collins, Francis S %A Dedoussis, George %A Dehghan, Abbas %A Deloukas, Panos %A Ferrario, Marco M %A Ferrieres, Jean %A Florez, Jose C %A Frossard, Philippe %A Gudnason, Vilmundur %A Harris, Tamara B %A Heckbert, Susan R %A Howson, Joanna M M %A Ingelsson, Martin %A Kathiresan, Sekar %A Kee, Frank %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lindgren, Cecilia M %A Männistö, Satu %A Meitinger, Thomas %A Melander, Olle %A Mohlke, Karen L %A Moitry, Marie %A Morris, Andrew D %A Murray, Alison D %A de Mutsert, Renée %A Orho-Melander, Marju %A Owen, Katharine R %A Perola, Markus %A Peters, Annette %A Province, Michael A %A Rasheed, Asif %A Ridker, Paul M %A Rivadineira, Fernando %A Rosendaal, Frits R %A Rosengren, Anders H %A Salomaa, Veikko %A Sheu, Wayne H-H %A Sladek, Rob %A Smith, Blair H %A Strauch, Konstantin %A Uitterlinden, André G %A Varma, Rohit %A Willer, Cristen J %A Blüher, Matthias %A Butterworth, Adam S %A Chambers, John Campbell %A Chasman, Daniel I %A Danesh, John %A van Duijn, Cornelia %A Dupuis, Josée %A Franco, Oscar H %A Franks, Paul W %A Froguel, Philippe %A Grallert, Harald %A Groop, Leif %A Han, Bok-Ghee %A Hansen, Torben %A Hattersley, Andrew T %A Hayward, Caroline %A Ingelsson, Erik %A Kardia, Sharon L R %A Karpe, Fredrik %A Kooner, Jaspal Singh %A Köttgen, Anna %A Kuulasmaa, Kari %A Laakso, Markku %A Lin, Xu %A Lind, Lars %A Liu, Yongmei %A Loos, Ruth J F %A Marchini, Jonathan %A Metspalu, Andres %A Mook-Kanamori, Dennis %A Nordestgaard, Børge G %A Palmer, Colin N A %A Pankow, James S %A Pedersen, Oluf %A Psaty, Bruce M %A Rauramaa, Rainer %A Sattar, Naveed %A Schulze, Matthias B %A Soranzo, Nicole %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Thorsteinsdottir, Unnur %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Wareham, Nicholas J %A Wilson, James G %A Zeggini, Eleftheria %A Scott, Robert A %A Barroso, Inês %A Frayling, Timothy M %A Goodarzi, Mark O %A Meigs, James B %A Boehnke, Michael %A Saleheen, Danish %A Morris, Andrew P %A Rotter, Jerome I %A McCarthy, Mark I %K Alleles %K Chromosome Mapping %K Diabetes Mellitus, Type 2 %K Exome Sequencing %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K White People %X

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

%B Nat Genet %V 50 %P 559-571 %8 2018 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/29632382?dopt=Abstract %R 10.1038/s41588-018-0084-1 %0 Journal Article %J Nature %D 2017 %T Rare and low-frequency coding variants alter human adult height. %A Marouli, Eirini %A Graff, Mariaelisa %A Medina-Gomez, Carolina %A Lo, Ken Sin %A Wood, Andrew R %A Kjaer, Troels R %A Fine, Rebecca S %A Lu, Yingchang %A Schurmann, Claudia %A Highland, Heather M %A Rüeger, Sina %A Thorleifsson, Gudmar %A Justice, Anne E %A Lamparter, David %A Stirrups, Kathleen E %A Turcot, Valérie %A Young, Kristin L %A Winkler, Thomas W %A Esko, Tõnu %A Karaderi, Tugce %A Locke, Adam E %A Masca, Nicholas G D %A Ng, Maggie C Y %A Mudgal, Poorva %A Rivas, Manuel A %A Vedantam, Sailaja %A Mahajan, Anubha %A Guo, Xiuqing %A Abecasis, Goncalo %A Aben, Katja K %A Adair, Linda S %A Alam, Dewan S %A Albrecht, Eva %A Allin, Kristine H %A Allison, Matthew %A Amouyel, Philippe %A Appel, Emil V %A Arveiler, Dominique %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Banas, Bernhard %A Bang, Lia E %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boeing, Heiner %A Boerwinkle, Eric %A Böger, Carsten A %A Bonnycastle, Lori L %A Bork-Jensen, Jette %A Bots, Michiel L %A Bottinger, Erwin P %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Burt, Amber A %A Butterworth, Adam S %A Carey, David J %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Galbany, Jordi Corominas %A Cox, Amanda J %A Cuellar-Partida, Gabriel %A Danesh, John %A Davies, Gail %A de Bakker, Paul I W %A de Borst, Gert J %A de Denus, Simon %A de Groot, Mark C H %A de Mutsert, Renée %A Deary, Ian J %A Dedoussis, George %A Demerath, Ellen W %A den Hollander, Anneke I %A Dennis, Joe G %A Di Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dunning, Alison M %A Easton, Douglas F %A Ebeling, Tapani %A Edwards, Todd L %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Faul, Jessica D %A Feitosa, Mary F %A Feng, Shuang %A Ferrannini, Ele %A Ferrario, Marco M %A Ferrieres, Jean %A Florez, Jose C %A Ford, Ian %A Fornage, Myriam %A Franks, Paul W %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Giri, Ayush %A Girotto, Giorgia %A Gordon, Scott D %A Gordon-Larsen, Penny %A Gorski, Mathias %A Grarup, Niels %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Hansen, Torben %A Harris, Kathleen Mullan %A Harris, Tamara B %A Hattersley, Andrew T %A Hayward, Caroline %A He, Liang %A Heid, Iris M %A Heikkilä, Kauko %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Hocking, Lynne J %A Hollensted, Mette %A Holmen, Oddgeir L %A Hovingh, G Kees %A Howson, Joanna M M %A Hoyng, Carel B %A Huang, Paul L %A Hveem, Kristian %A Ikram, M Arfan %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jhun, Min A %A Jia, Yucheng %A Jiang, Xuejuan %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jousilahti, Pekka %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Kardia, Sharon L R %A Karpe, Fredrik %A Kee, Frank %A Keeman, Renske %A Kiemeney, Lambertus A %A Kitajima, Hidetoshi %A Kluivers, Kirsten B %A Kocher, Thomas %A Komulainen, Pirjo %A Kontto, Jukka %A Kooner, Jaspal S %A Kooperberg, Charles %A Kovacs, Peter %A Kriebel, Jennifer %A Kuivaniemi, Helena %A Küry, Sébastien %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lakka, Timo A %A Lange, Ethan M %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Larson, Eric B %A Lee, I-Te %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Li-An %A Lin, Xu %A Lind, Lars %A Lindström, Jaana %A Linneberg, Allan %A Liu, Yeheng %A Liu, Yongmei %A Lophatananon, Artitaya %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Mackey, David A %A Madden, Pamela A F %A Manning, Alisa K %A Männistö, Satu %A Marenne, Gaëlle %A Marten, Jonathan %A Martin, Nicholas G %A Mazul, Angela L %A Meidtner, Karina %A Metspalu, Andres %A Mitchell, Paul %A Mohlke, Karen L %A Mook-Kanamori, Dennis O %A Morgan, Anna %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Nalls, Mike A %A Nauck, Matthias %A Nelson, Christopher P %A Neville, Matt %A Nielsen, Sune F %A Nikus, Kjell %A Njølstad, Pål R %A Nordestgaard, Børge G %A Ntalla, Ioanna %A O'Connel, Jeffrey R %A Oksa, Heikki %A Loohuis, Loes M Olde %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Perola, Markus %A Perry, James A %A Perry, John R B %A Person, Thomas N %A Pirie, Ailith %A Polasek, Ozren %A Posthuma, Danielle %A Raitakari, Olli T %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Reiner, Alex P %A Renstrom, Frida %A Ridker, Paul M %A Rioux, John D %A Robertson, Neil %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Salomaa, Veikko %A Samani, Nilesh J %A Sandow, Kevin %A Sapkota, Yadav %A Sattar, Naveed %A Schmidt, Marjanka K %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Shah, Svati %A Sim, Xueling %A Sivapalaratnam, Suthesh %A Small, Kerrin S %A Smith, Albert Vernon %A Smith, Jennifer A %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Steinthorsdottir, Valgerdur %A Stringham, Heather M %A Stumvoll, Michael %A Surendran, Praveen %A 't Hart, Leen M %A Tansey, Katherine E %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thompson, Deborah J %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tonjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A Uitterlinden, André G %A Ulivi, Sheila %A van der Laan, Sander W %A Van Der Leij, Andries R %A van Duijn, Cornelia M %A van Schoor, Natasja M %A van Setten, Jessica %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Edwards, Digna R Velez %A Vermeulen, Sita H %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Vozzi, Diego %A Walker, Mark %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Wareham, Nicholas J %A Warren, Helen R %A Wessel, Jennifer %A Willems, Sara M %A Wilson, James G %A Witte, Daniel R %A Woods, Michael O %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Yerges-Armstrong, Laura M %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhao, Wei %A Zhao, Wei %A Zheng, He %A Zhou, Wei %A Rotter, Jerome I %A Boehnke, Michael %A Kathiresan, Sekar %A McCarthy, Mark I %A Willer, Cristen J %A Stefansson, Kari %A Borecki, Ingrid B %A Liu, Dajiang J %A North, Kari E %A Heard-Costa, Nancy L %A Pers, Tune H %A Lindgren, Cecilia M %A Oxvig, Claus %A Kutalik, Zoltán %A Rivadeneira, Fernando %A Loos, Ruth J F %A Frayling, Timothy M %A Hirschhorn, Joel N %A Deloukas, Panos %A Lettre, Guillaume %K ADAMTS Proteins %K Adult %K Alleles %K Body Height %K Cell Adhesion Molecules %K Female %K Gene Frequency %K Genetic Variation %K Genome, Human %K Glycoproteins %K Glycosaminoglycans %K Hedgehog Proteins %K Humans %K Intercellular Signaling Peptides and Proteins %K Interferon Regulatory Factors %K Interleukin-11 Receptor alpha Subunit %K Male %K Multifactorial Inheritance %K NADPH Oxidase 4 %K NADPH Oxidases %K Phenotype %K Pregnancy-Associated Plasma Protein-A %K Procollagen N-Endopeptidase %K Proteoglycans %K Proteolysis %K Receptors, Androgen %K Somatomedins %X

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

%B Nature %V 542 %P 186-190 %8 2017 Feb 09 %G eng %N 7640 %1 https://www.ncbi.nlm.nih.gov/pubmed/28146470?dopt=Abstract %R 10.1038/nature21039 %0 Journal Article %J Am J Hum Genet %D 2016 %T Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits. %A Chami, Nathalie %A Chen, Ming-Huei %A Slater, Andrew J %A Eicher, John D %A Evangelou, Evangelos %A Tajuddin, Salman M %A Love-Gregory, Latisha %A Kacprowski, Tim %A Schick, Ursula M %A Nomura, Akihiro %A Giri, Ayush %A Lessard, Samuel %A Brody, Jennifer A %A Schurmann, Claudia %A Pankratz, Nathan %A Yanek, Lisa R %A Manichaikul, Ani %A Pazoki, Raha %A Mihailov, Evelin %A Hill, W David %A Raffield, Laura M %A Burt, Amber %A Bartz, Traci M %A Becker, Diane M %A Becker, Lewis C %A Boerwinkle, Eric %A Bork-Jensen, Jette %A Bottinger, Erwin P %A O'Donoghue, Michelle L %A Crosslin, David R %A de Denus, Simon %A Dube, Marie-Pierre %A Elliott, Paul %A Engström, Gunnar %A Evans, Michele K %A Floyd, James S %A Fornage, Myriam %A Gao, He %A Greinacher, Andreas %A Gudnason, Vilmundur %A Hansen, Torben %A Harris, Tamara B %A Hayward, Caroline %A Hernesniemi, Jussi %A Highland, Heather M %A Hirschhorn, Joel N %A Hofman, Albert %A Irvin, Marguerite R %A Kähönen, Mika %A Lange, Ethan %A Launer, Lenore J %A Lehtimäki, Terho %A Li, Jin %A Liewald, David C M %A Linneberg, Allan %A Liu, Yongmei %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Mathias, Rasika A %A Melander, Olle %A Metspalu, Andres %A Mononen, Nina %A Nalls, Mike A %A Nickerson, Deborah A %A Nikus, Kjell %A O'Donnell, Chris J %A Orho-Melander, Marju %A Pedersen, Oluf %A Petersmann, Astrid %A Polfus, Linda %A Psaty, Bruce M %A Raitakari, Olli T %A Raitoharju, Emma %A Richard, Melissa %A Rice, Kenneth M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Schmidt, Frank %A Smith, Albert Vernon %A Starr, John M %A Taylor, Kent D %A Teumer, Alexander %A Thuesen, Betina H %A Torstenson, Eric S %A Tracy, Russell P %A Tzoulaki, Ioanna %A Zakai, Neil A %A Vacchi-Suzzi, Caterina %A van Duijn, Cornelia M %A van Rooij, Frank J A %A Cushman, Mary %A Deary, Ian J %A Velez Edwards, Digna R %A Vergnaud, Anne-Claire %A Wallentin, Lars %A Waterworth, Dawn M %A White, Harvey D %A Wilson, James G %A Zonderman, Alan B %A Kathiresan, Sekar %A Grarup, Niels %A Esko, Tõnu %A Loos, Ruth J F %A Lange, Leslie A %A Faraday, Nauder %A Abumrad, Nada A %A Edwards, Todd L %A Ganesh, Santhi K %A Auer, Paul L %A Johnson, Andrew D %A Reiner, Alexander P %A Lettre, Guillaume %K Allelic Imbalance %K Black or African American %K Erythrocyte Indices %K Erythrocytes %K Erythropoiesis %K Exome %K Gene Frequency %K Genetic Pleiotropy %K Genetic Variation %K Genotype %K Hematocrit %K Hemoglobins %K Humans %K Quantitative Trait Loci %X

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

%B Am J Hum Genet %V 99 %P 8-21 %8 2016 Jul 07 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/27346685?dopt=Abstract %R 10.1016/j.ajhg.2016.05.007 %0 Journal Article %J Am J Hum Genet %D 2016 %T Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. %A Tajuddin, Salman M %A Schick, Ursula M %A Eicher, John D %A Chami, Nathalie %A Giri, Ayush %A Brody, Jennifer A %A Hill, W David %A Kacprowski, Tim %A Li, Jin %A Lyytikäinen, Leo-Pekka %A Manichaikul, Ani %A Mihailov, Evelin %A O'Donoghue, Michelle L %A Pankratz, Nathan %A Pazoki, Raha %A Polfus, Linda M %A Smith, Albert Vernon %A Schurmann, Claudia %A Vacchi-Suzzi, Caterina %A Waterworth, Dawn M %A Evangelou, Evangelos %A Yanek, Lisa R %A Burt, Amber %A Chen, Ming-Huei %A van Rooij, Frank J A %A Floyd, James S %A Greinacher, Andreas %A Harris, Tamara B %A Highland, Heather M %A Lange, Leslie A %A Liu, Yongmei %A Mägi, Reedik %A Nalls, Mike A %A Mathias, Rasika A %A Nickerson, Deborah A %A Nikus, Kjell %A Starr, John M %A Tardif, Jean-Claude %A Tzoulaki, Ioanna %A Velez Edwards, Digna R %A Wallentin, Lars %A Bartz, Traci M %A Becker, Lewis C %A Denny, Joshua C %A Raffield, Laura M %A Rioux, John D %A Friedrich, Nele %A Fornage, Myriam %A Gao, He %A Hirschhorn, Joel N %A Liewald, David C M %A Rich, Stephen S %A Uitterlinden, Andre %A Bastarache, Lisa %A Becker, Diane M %A Boerwinkle, Eric %A de Denus, Simon %A Bottinger, Erwin P %A Hayward, Caroline %A Hofman, Albert %A Homuth, Georg %A Lange, Ethan %A Launer, Lenore J %A Lehtimäki, Terho %A Lu, Yingchang %A Metspalu, Andres %A O'Donnell, Chris J %A Quarells, Rakale C %A Richard, Melissa %A Torstenson, Eric S %A Taylor, Kent D %A Vergnaud, Anne-Claire %A Zonderman, Alan B %A Crosslin, David R %A Deary, Ian J %A Dörr, Marcus %A Elliott, Paul %A Evans, Michele K %A Gudnason, Vilmundur %A Kähönen, Mika %A Psaty, Bruce M %A Rotter, Jerome I %A Slater, Andrew J %A Dehghan, Abbas %A White, Harvey D %A Ganesh, Santhi K %A Loos, Ruth J F %A Esko, Tõnu %A Faraday, Nauder %A Wilson, James G %A Cushman, Mary %A Johnson, Andrew D %A Edwards, Todd L %A Zakai, Neil A %A Lettre, Guillaume %A Reiner, Alex P %A Auer, Paul L %K Blood Cell Count %K Exome %K Genetic Loci %K Genetic Pleiotropy %K Genome-Wide Association Study %K Humans %K Immune System Diseases %K Leukocytes %K Quality Control %X

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

%B Am J Hum Genet %V 99 %P 22-39 %8 2016 Jul 07 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/27346689?dopt=Abstract %R 10.1016/j.ajhg.2016.05.003 %0 Journal Article %J Am J Hum Genet %D 2016 %T Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals. %A Eicher, John D %A Chami, Nathalie %A Kacprowski, Tim %A Nomura, Akihiro %A Chen, Ming-Huei %A Yanek, Lisa R %A Tajuddin, Salman M %A Schick, Ursula M %A Slater, Andrew J %A Pankratz, Nathan %A Polfus, Linda %A Schurmann, Claudia %A Giri, Ayush %A Brody, Jennifer A %A Lange, Leslie A %A Manichaikul, Ani %A Hill, W David %A Pazoki, Raha %A Elliot, Paul %A Evangelou, Evangelos %A Tzoulaki, Ioanna %A Gao, He %A Vergnaud, Anne-Claire %A Mathias, Rasika A %A Becker, Diane M %A Becker, Lewis C %A Burt, Amber %A Crosslin, David R %A Lyytikäinen, Leo-Pekka %A Nikus, Kjell %A Hernesniemi, Jussi %A Kähönen, Mika %A Raitoharju, Emma %A Mononen, Nina %A Raitakari, Olli T %A Lehtimäki, Terho %A Cushman, Mary %A Zakai, Neil A %A Nickerson, Deborah A %A Raffield, Laura M %A Quarells, Rakale %A Willer, Cristen J %A Peloso, Gina M %A Abecasis, Gonçalo R %A Liu, Dajiang J %A Deloukas, Panos %A Samani, Nilesh J %A Schunkert, Heribert %A Erdmann, Jeanette %A Fornage, Myriam %A Richard, Melissa %A Tardif, Jean-Claude %A Rioux, John D %A Dube, Marie-Pierre %A de Denus, Simon %A Lu, Yingchang %A Bottinger, Erwin P %A Loos, Ruth J F %A Smith, Albert Vernon %A Harris, Tamara B %A Launer, Lenore J %A Gudnason, Vilmundur %A Velez Edwards, Digna R %A Torstenson, Eric S %A Liu, Yongmei %A Tracy, Russell P %A Rotter, Jerome I %A Rich, Stephen S %A Highland, Heather M %A Boerwinkle, Eric %A Li, Jin %A Lange, Ethan %A Wilson, James G %A Mihailov, Evelin %A Mägi, Reedik %A Hirschhorn, Joel %A Metspalu, Andres %A Esko, Tõnu %A Vacchi-Suzzi, Caterina %A Nalls, Mike A %A Zonderman, Alan B %A Evans, Michele K %A Engström, Gunnar %A Orho-Melander, Marju %A Melander, Olle %A O'Donoghue, Michelle L %A Waterworth, Dawn M %A Wallentin, Lars %A White, Harvey D %A Floyd, James S %A Bartz, Traci M %A Rice, Kenneth M %A Psaty, Bruce M %A Starr, J M %A Liewald, David C M %A Hayward, Caroline %A Deary, Ian J %A Greinacher, Andreas %A Völker, Uwe %A Thiele, Thomas %A Völzke, Henry %A van Rooij, Frank J A %A Uitterlinden, André G %A Franco, Oscar H %A Dehghan, Abbas %A Edwards, Todd L %A Ganesh, Santhi K %A Kathiresan, Sekar %A Faraday, Nauder %A Auer, Paul L %A Reiner, Alex P %A Lettre, Guillaume %A Johnson, Andrew D %K Blood Platelets %K Exome %K Female %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Mean Platelet Volume %K Platelet Count %X

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

%B Am J Hum Genet %V 99 %P 40-55 %8 2016 Jul 07 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/27346686?dopt=Abstract %R 10.1016/j.ajhg.2016.05.005 %0 Journal Article %J Nature %D 2007 %T Genome-wide detection and characterization of positive selection in human populations. %A Sabeti, Pardis C %A Varilly, Patrick %A Fry, Ben %A Lohmueller, Jason %A Hostetter, Elizabeth %A Cotsapas, Chris %A Xie, Xiaohui %A Byrne, Elizabeth H %A McCarroll, Steven A %A Gaudet, Rachelle %A Schaffner, Stephen F %A Lander, Eric S %A Frazer, Kelly A %A Ballinger, Dennis G %A Cox, David R %A Hinds, David A %A Stuve, Laura L %A Gibbs, Richard A %A Belmont, John W %A Boudreau, Andrew %A Hardenbol, Paul %A Leal, Suzanne M %A Pasternak, Shiran %A Wheeler, David A %A Willis, Thomas D %A Yu, Fuli %A Yang, Huanming %A Zeng, Changqing %A Gao, Yang %A Hu, Haoran %A Hu, Weitao %A Li, Chaohua %A Lin, Wei %A Liu, Siqi %A Pan, Hao %A Tang, Xiaoli %A Wang, Jian %A Wang, Wei %A Yu, Jun %A Zhang, Bo %A Zhang, Qingrun %A Zhao, Hongbin %A Zhao, Hui %A Zhou, Jun %A Gabriel, Stacey B %A Barry, Rachel %A Blumenstiel, Brendan %A Camargo, Amy %A Defelice, Matthew %A Faggart, Maura %A Goyette, Mary %A Gupta, Supriya %A Moore, Jamie %A Nguyen, Huy %A Onofrio, Robert C %A Parkin, Melissa %A Roy, Jessica %A Stahl, Erich %A Winchester, Ellen %A Ziaugra, Liuda %A Altshuler, David %A Shen, Yan %A Yao, Zhijian %A Huang, Wei %A Chu, Xun %A He, Yungang %A Jin, Li %A Liu, Yangfan %A Shen, Yayun %A Sun, Weiwei %A Wang, Haifeng %A Wang, Yi %A Wang, Ying %A Xiong, Xiaoyan %A Xu, Liang %A Waye, Mary M Y %A Tsui, Stephen K W %A Xue, Hong %A Wong, J Tze-Fei %A Galver, Luana M %A Fan, Jian-Bing %A Gunderson, Kevin %A Murray, Sarah S %A Oliphant, Arnold R %A Chee, Mark S %A Montpetit, Alexandre %A Chagnon, Fanny %A Ferretti, Vincent %A Leboeuf, Martin %A Olivier, Jean-François %A Phillips, Michael S %A Roumy, Stéphanie %A Sallée, Clémentine %A Verner, Andrei %A Hudson, Thomas J %A Kwok, Pui-Yan %A Cai, Dongmei %A Koboldt, Daniel C %A Miller, Raymond D %A Pawlikowska, Ludmila %A Taillon-Miller, Patricia %A Xiao, Ming %A Tsui, Lap-Chee %A Mak, William %A Song, You Qiang %A Tam, Paul K H %A Nakamura, Yusuke %A Kawaguchi, Takahisa %A Kitamoto, Takuya %A Morizono, Takashi %A Nagashima, Atsushi %A Ohnishi, Yozo %A Sekine, Akihiro %A Tanaka, Toshihiro %A Tsunoda, Tatsuhiko %A Deloukas, Panos %A Bird, Christine P %A Delgado, Marcos %A Dermitzakis, Emmanouil T %A Gwilliam, Rhian %A Hunt, Sarah %A Morrison, Jonathan %A Powell, Don %A Stranger, Barbara E %A Whittaker, Pamela %A Bentley, David R %A Daly, Mark J %A de Bakker, Paul I W %A Barrett, Jeff %A Chretien, Yves R %A Maller, Julian %A McCarroll, Steve %A Patterson, Nick %A Pe'er, Itsik %A Price, Alkes %A Purcell, Shaun %A Richter, Daniel J %A Sabeti, Pardis %A Saxena, Richa %A Schaffner, Stephen F %A Sham, Pak C %A Varilly, Patrick %A Altshuler, David %A Stein, Lincoln D %A Krishnan, Lalitha %A Smith, Albert Vernon %A Tello-Ruiz, Marcela K %A Thorisson, Gudmundur A %A Chakravarti, Aravinda %A Chen, Peter E %A Cutler, David J %A Kashuk, Carl S %A Lin, Shin %A Abecasis, Gonçalo R %A Guan, Weihua %A Li, Yun %A Munro, Heather M %A Qin, Zhaohui Steve %A Thomas, Daryl J %A McVean, Gilean %A Auton, Adam %A Bottolo, Leonardo %A Cardin, Niall %A Eyheramendy, Susana %A Freeman, Colin %A Marchini, Jonathan %A Myers, Simon %A Spencer, Chris %A Stephens, Matthew %A Donnelly, Peter %A Cardon, Lon R %A Clarke, Geraldine %A Evans, David M %A Morris, Andrew P %A Weir, Bruce S %A Tsunoda, Tatsuhiko %A Johnson, Todd A %A Mullikin, James C %A Sherry, Stephen T %A Feolo, Michael %A Skol, Andrew %A Zhang, Houcan %A Zeng, Changqing %A Zhao, Hui %A Matsuda, Ichiro %A Fukushima, Yoshimitsu %A Macer, Darryl R %A Suda, Eiko %A Rotimi, Charles N %A Adebamowo, Clement A %A Ajayi, Ike %A Aniagwu, Toyin %A Marshall, Patricia A %A Nkwodimmah, Chibuzor %A Royal, Charmaine D M %A Leppert, Mark F %A Dixon, Missy %A Peiffer, Andy %A Qiu, Renzong %A Kent, Alastair %A Kato, Kazuto %A Niikawa, Norio %A Adewole, Isaac F %A Knoppers, Bartha M %A Foster, Morris W %A Clayton, Ellen Wright %A Watkin, Jessica %A Gibbs, Richard A %A Belmont, John W %A Muzny, Donna %A Nazareth, Lynne %A Sodergren, Erica %A Weinstock, George M %A Wheeler, David A %A Yakub, Imtaz %A Gabriel, Stacey B %A Onofrio, Robert C %A Richter, Daniel J %A Ziaugra, Liuda %A Birren, Bruce W %A Daly, Mark J %A Altshuler, David %A Wilson, Richard K %A Fulton, Lucinda L %A Rogers, Jane %A Burton, John %A Carter, Nigel P %A Clee, Christopher M %A Griffiths, Mark %A Jones, Matthew C %A McLay, Kirsten %A Plumb, Robert W %A Ross, Mark T %A Sims, Sarah K %A Willey, David L %A Chen, Zhu %A Han, Hua %A Kang, Le %A Godbout, Martin %A Wallenburg, John C %A L'Archevêque, Paul %A Bellemare, Guy %A Saeki, Koji %A Wang, Hongguang %A An, Daochang %A Fu, Hongbo %A Li, Qing %A Wang, Zhen %A Wang, Renwu %A Holden, Arthur L %A Brooks, Lisa D %A McEwen, Jean E %A Guyer, Mark S %A Wang, Vivian Ota %A Peterson, Jane L %A Shi, Michael %A Spiegel, Jack %A Sung, Lawrence M %A Zacharia, Lynn F %A Collins, Francis S %A Kennedy, Karen %A Jamieson, Ruth %A Stewart, John %K Antiporters %K Edar Receptor %K Gene Frequency %K Genetics, Population %K Genome, Human %K Geography %K Haplotypes %K Humans %K Models, Molecular %K Polymorphism, Single Nucleotide %K Protein Structure, Tertiary %K Selection, Genetic %X

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

%B Nature %V 449 %P 913-8 %8 2007 Oct 18 %G eng %N 7164 %1 https://www.ncbi.nlm.nih.gov/pubmed/17943131?dopt=Abstract %R 10.1038/nature06250 %0 Journal Article %J Nature %D 2007 %T A second generation human haplotype map of over 3.1 million SNPs. %A Frazer, Kelly A %A Ballinger, Dennis G %A Cox, David R %A Hinds, David A %A Stuve, Laura L %A Gibbs, Richard A %A Belmont, John W %A Boudreau, Andrew %A Hardenbol, Paul %A Leal, Suzanne M %A Pasternak, Shiran %A Wheeler, David A %A Willis, Thomas D %A Yu, Fuli %A Yang, Huanming %A Zeng, Changqing %A Gao, Yang %A Hu, Haoran %A Hu, Weitao %A Li, Chaohua %A Lin, Wei %A Liu, Siqi %A Pan, Hao %A Tang, Xiaoli %A Wang, Jian %A Wang, Wei %A Yu, Jun %A Zhang, Bo %A Zhang, Qingrun %A Zhao, Hongbin %A Zhao, Hui %A Zhou, Jun %A Gabriel, Stacey B %A Barry, Rachel %A Blumenstiel, Brendan %A Camargo, Amy %A Defelice, Matthew %A Faggart, Maura %A Goyette, Mary %A Gupta, Supriya %A Moore, Jamie %A Nguyen, Huy %A Onofrio, Robert C %A Parkin, Melissa %A Roy, Jessica %A Stahl, Erich %A Winchester, Ellen %A Ziaugra, Liuda %A Altshuler, David %A Shen, Yan %A Yao, Zhijian %A Huang, Wei %A Chu, Xun %A He, Yungang %A Jin, Li %A Liu, Yangfan %A Shen, Yayun %A Sun, Weiwei %A Wang, Haifeng %A Wang, Yi %A Wang, Ying %A Xiong, Xiaoyan %A Xu, Liang %A Waye, Mary M Y %A Tsui, Stephen K W %A Xue, Hong %A Wong, J Tze-Fei %A Galver, Luana M %A Fan, Jian-Bing %A Gunderson, Kevin %A Murray, Sarah S %A Oliphant, Arnold R %A Chee, Mark S %A Montpetit, Alexandre %A Chagnon, Fanny %A Ferretti, Vincent %A Leboeuf, Martin %A Olivier, Jean-François %A Phillips, Michael S %A Roumy, Stéphanie %A Sallée, Clémentine %A Verner, Andrei %A Hudson, Thomas J %A Kwok, Pui-Yan %A Cai, Dongmei %A Koboldt, Daniel C %A Miller, Raymond D %A Pawlikowska, Ludmila %A Taillon-Miller, Patricia %A Xiao, Ming %A Tsui, Lap-Chee %A Mak, William %A Song, You Qiang %A Tam, Paul K H %A Nakamura, Yusuke %A Kawaguchi, Takahisa %A Kitamoto, Takuya %A Morizono, Takashi %A Nagashima, Atsushi %A Ohnishi, Yozo %A Sekine, Akihiro %A Tanaka, Toshihiro %A Tsunoda, Tatsuhiko %A Deloukas, Panos %A Bird, Christine P %A Delgado, Marcos %A Dermitzakis, Emmanouil T %A Gwilliam, Rhian %A Hunt, Sarah %A Morrison, Jonathan %A Powell, Don %A Stranger, Barbara E %A Whittaker, Pamela %A Bentley, David R %A Daly, Mark J %A de Bakker, Paul I W %A Barrett, Jeff %A Chretien, Yves R %A Maller, Julian %A McCarroll, Steve %A Patterson, Nick %A Pe'er, Itsik %A Price, Alkes %A Purcell, Shaun %A Richter, Daniel J %A Sabeti, Pardis %A Saxena, Richa %A Schaffner, Stephen F %A Sham, Pak C %A Varilly, Patrick %A Altshuler, David %A Stein, Lincoln D %A Krishnan, Lalitha %A Smith, Albert Vernon %A Tello-Ruiz, Marcela K %A Thorisson, Gudmundur A %A Chakravarti, Aravinda %A Chen, Peter E %A Cutler, David J %A Kashuk, Carl S %A Lin, Shin %A Abecasis, Gonçalo R %A Guan, Weihua %A Li, Yun %A Munro, Heather M %A Qin, Zhaohui Steve %A Thomas, Daryl J %A McVean, Gilean %A Auton, Adam %A Bottolo, Leonardo %A Cardin, Niall %A Eyheramendy, Susana %A Freeman, Colin %A Marchini, Jonathan %A Myers, Simon %A Spencer, Chris %A Stephens, Matthew %A Donnelly, Peter %A Cardon, Lon R %A Clarke, Geraldine %A Evans, David M %A Morris, Andrew P %A Weir, Bruce S %A Tsunoda, Tatsuhiko %A Mullikin, James C %A Sherry, Stephen T %A Feolo, Michael %A Skol, Andrew %A Zhang, Houcan %A Zeng, Changqing %A Zhao, Hui %A Matsuda, Ichiro %A Fukushima, Yoshimitsu %A Macer, Darryl R %A Suda, Eiko %A Rotimi, Charles N %A Adebamowo, Clement A %A Ajayi, Ike %A Aniagwu, Toyin %A Marshall, Patricia A %A Nkwodimmah, Chibuzor %A Royal, Charmaine D M %A Leppert, Mark F %A Dixon, Missy %A Peiffer, Andy %A Qiu, Renzong %A Kent, Alastair %A Kato, Kazuto %A Niikawa, Norio %A Adewole, Isaac F %A Knoppers, Bartha M %A Foster, Morris W %A Clayton, Ellen Wright %A Watkin, Jessica %A Gibbs, Richard A %A Belmont, John W %A Muzny, Donna %A Nazareth, Lynne %A Sodergren, Erica %A Weinstock, George M %A Wheeler, David A %A Yakub, Imtaz %A Gabriel, Stacey B %A Onofrio, Robert C %A Richter, Daniel J %A Ziaugra, Liuda %A Birren, Bruce W %A Daly, Mark J %A Altshuler, David %A Wilson, Richard K %A Fulton, Lucinda L %A Rogers, Jane %A Burton, John %A Carter, Nigel P %A Clee, Christopher M %A Griffiths, Mark %A Jones, Matthew C %A McLay, Kirsten %A Plumb, Robert W %A Ross, Mark T %A Sims, Sarah K %A Willey, David L %A Chen, Zhu %A Han, Hua %A Kang, Le %A Godbout, Martin %A Wallenburg, John C %A L'Archevêque, Paul %A Bellemare, Guy %A Saeki, Koji %A Wang, Hongguang %A An, Daochang %A Fu, Hongbo %A Li, Qing %A Wang, Zhen %A Wang, Renwu %A Holden, Arthur L %A Brooks, Lisa D %A McEwen, Jean E %A Guyer, Mark S %A Wang, Vivian Ota %A Peterson, Jane L %A Shi, Michael %A Spiegel, Jack %A Sung, Lawrence M %A Zacharia, Lynn F %A Collins, Francis S %A Kennedy, Karen %A Jamieson, Ruth %A Stewart, John %K Female %K Haplotypes %K Homozygote %K Humans %K Linkage Disequilibrium %K Male %K Polymorphism, Single Nucleotide %K Racial Groups %K Recombination, Genetic %K Selection, Genetic %X

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.

%B Nature %V 449 %P 851-61 %8 2007 Oct 18 %G eng %N 7164 %1 https://www.ncbi.nlm.nih.gov/pubmed/17943122?dopt=Abstract %R 10.1038/nature06258