%0 Journal Article %J Nat Genet %D 2019 %T Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. %A Justice, Anne E %A Karaderi, Tugce %A Highland, Heather M %A Young, Kristin L %A Graff, Mariaelisa %A Lu, Yingchang %A Turcot, Valérie %A Auer, Paul L %A Fine, Rebecca S %A Guo, Xiuqing %A Schurmann, Claudia %A Lempradl, Adelheid %A Marouli, Eirini %A Mahajan, Anubha %A Winkler, Thomas W %A Locke, Adam E %A Medina-Gomez, Carolina %A Esko, Tõnu %A Vedantam, Sailaja %A Giri, Ayush %A Lo, Ken Sin %A Alfred, Tamuno %A Mudgal, Poorva %A Ng, Maggie C Y %A Heard-Costa, Nancy L %A Feitosa, Mary F %A Manning, Alisa K %A Willems, Sara M %A Sivapalaratnam, Suthesh %A Abecasis, Goncalo %A Alam, Dewan S %A Allison, Matthew %A Amouyel, Philippe %A Arzumanyan, Zorayr %A Balkau, Beverley %A Bastarache, Lisa %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boehnke, Michael %A Boeing, Heiner %A Eric Boerwinkle %A Böger, Carsten A %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Bowden, Donald W %A Brandslund, Ivan %A Broer, Linda %A Burt, Amber A %A Butterworth, Adam S %A Caulfield, Mark J %A Cesana, Giancarlo %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Collins, Francis S %A Cook, James P %A Cox, Amanda J %A Crosslin, David S %A Danesh, John %A de Bakker, Paul I W %A Denus, Simon de %A Mutsert, Renée de %A Dedoussis, George %A Demerath, Ellen W %A Dennis, Joe G %A Denny, Josh C %A Di Angelantonio, Emanuele %A Dörr, Marcus %A Drenos, Fotios %A Dube, Marie-Pierre %A Dunning, Alison M %A Easton, Douglas F %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Feng, Shuang %A Ferrannini, Ele %A Ferrieres, Jean %A Florez, Jose C %A Fornage, Myriam %A Fox, Caroline S %A Franks, Paul W %A Friedrich, Nele %A Gan, Wei %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Girotto, Giorgia %A Gorski, Mathias %A Grallert, Harald %A Grarup, Niels %A Grove, Megan L %A Gustafsson, Stefan %A Haessler, Jeff %A Hansen, Torben %A Hattersley, Andrew T %A Hayward, Caroline %A Heid, Iris M %A Holmen, Oddgeir L %A Hovingh, G Kees %A Howson, Joanna M M %A Hu, Yao %A Hung, Yi-Jen %A Hveem, Kristian %A Ikram, M Arfan %A Ingelsson, Erik %A Jackson, Anne U %A Jarvik, Gail P %A Jia, Yucheng %A Jørgensen, Torben %A Jousilahti, Pekka %A Justesen, Johanne M %A Kahali, Bratati %A Karaleftheri, Maria %A Kardia, Sharon L R %A Karpe, Fredrik %A Kee, Frank %A Kitajima, Hidetoshi %A Komulainen, Pirjo %A Kooner, Jaspal S %A Kovacs, Peter %A Krämer, Bernhard K %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lamparter, David %A Lange, Leslie A %A Langenberg, Claudia %A Larson, Eric B %A Lee, Nanette R %A Lee, Wen-Jane %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Li-An %A Lin, Xu %A Lind, Lars %A Lindström, Jaana %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Dajiang J %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A MacGregor, Stuart %A Mägi, Reedik %A Männistö, Satu %A Marenne, Gaëlle %A Marten, Jonathan %A Masca, Nicholas G D %A McCarthy, Mark I %A Meidtner, Karina %A Mihailov, Evelin %A Moilanen, Leena %A Moitry, Marie %A Mook-Kanamori, Dennis O %A Morgan, Anna %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Narisu, Narisu %A Nelson, Christopher P %A Neville, Matt %A Ntalla, Ioanna %A O'Connell, Jeffrey R %A Owen, Katharine R %A Pedersen, Oluf %A Peloso, Gina M %A Pennell, Craig E %A Perola, Markus %A Perry, James A %A Perry, John R B %A Pers, Tune H %A Ewing, Ailith %A Polasek, Ozren %A Raitakari, Olli T %A Rasheed, Asif %A Raulerson, Chelsea K %A Rauramaa, Rainer %A Reilly, Dermot F %A Reiner, Alex P %A Ridker, Paul M %A Rivas, Manuel A %A Robertson, Neil R %A Robino, Antonietta %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Salomaa, Veikko %A Samani, Nilesh J %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo %A Sim, Xueling %A Slater, Andrew J %A Small, Kerrin S %A Smith, Blair H %A Smith, Jennifer A %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Stefansson, Kari %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen E %A Strauch, Konstantin %A Stringham, Heather M %A Stumvoll, Michael %A Sun, Liang %A Surendran, Praveen %A Swart, Karin M A %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thompson, Deborah J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tonjes, Anke %A Torres, Mina %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A van Duijn, Cornelia M %A Vanhala, Mauno %A Varma, Rohit %A Vermeulen, Sita H %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Vuckovic, Dragana %A Wagenknecht, Lynne E %A Walker, Mark %A Wallentin, Lars %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wareham, Nicholas J %A Warren, Helen R %A Waterworth, Dawn M %A Wessel, Jennifer %A White, Harvey D %A Willer, Cristen J %A Wilson, James G %A Wood, Andrew R %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %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 Zheng, He %A Zhou, Wei %A Zillikens, M Carola %A Rivadeneira, Fernando %A Borecki, Ingrid B %A Pospisilik, J Andrew %A Deloukas, Panos %A Frayling, Timothy M %A Lettre, Guillaume %A Mohlke, Karen L %A Rotter, Jerome I %A Kutalik, Zoltán %A Hirschhorn, Joel N %A Cupples, L Adrienne %A Loos, Ruth J F %A North, Kari E %A Lindgren, Cecilia M %K Animals %K Body Fat Distribution %K Body Mass Index %K Case-Control Studies %K Drosophila %K Exome %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Homeostasis %K Humans %K Lipids %K Male %K Proteins %K Risk Factors %K Waist-Hip Ratio %X

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

%B Nat Genet %V 51 %P 452-469 %8 2019 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/30778226?dopt=Abstract %R 10.1038/s41588-018-0334-2 %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 Nat Commun %D 2015 %T Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. %A Wessel, Jennifer %A Chu, Audrey Y %A Willems, Sara M %A Wang, Shuai %A Yaghootkar, Hanieh %A Brody, Jennifer A %A Dauriz, Marco %A Hivert, Marie-France %A Raghavan, Sridharan %A Lipovich, Leonard %A Hidalgo, Bertha %A Fox, Keolu %A Huffman, Jennifer E %A An, Ping %A Lu, Yingchang %A Rasmussen-Torvik, Laura J %A Grarup, Niels %A Ehm, Margaret G %A Li, Li %A Baldridge, Abigail S %A Stančáková, Alena %A Abrol, Ravinder %A Besse, Céline %A Boland, Anne %A Bork-Jensen, Jette %A Fornage, Myriam %A Freitag, Daniel F %A Garcia, Melissa E %A Guo, Xiuqing %A Hara, Kazuo %A Isaacs, Aaron %A Jakobsdottir, Johanna %A Lange, Leslie A %A Layton, Jill C %A Li, Man %A Hua Zhao, Jing %A Meidtner, Karina %A Morrison, Alanna C %A Nalls, Mike A %A Peters, Marjolein J %A Sabater-Lleal, Maria %A Schurmann, Claudia %A Silveira, Angela %A Smith, Albert V %A Southam, Lorraine %A Stoiber, Marcus H %A Strawbridge, Rona J %A Taylor, Kent D %A Varga, Tibor V %A Allin, Kristine H %A Amin, Najaf %A Aponte, Jennifer L %A Aung, Tin %A Barbieri, Caterina %A Bihlmeyer, Nathan A %A Boehnke, Michael %A Bombieri, Cristina %A Bowden, Donald W %A Burns, Sean M %A Chen, Yuning %A Chen, Yii-DerI %A Cheng, Ching-Yu %A Correa, Adolfo %A Czajkowski, Jacek %A Dehghan, Abbas %A Ehret, Georg B %A Eiriksdottir, Gudny %A Escher, Stefan A %A Farmaki, Aliki-Eleni %A Frånberg, Mattias %A Gambaro, Giovanni %A Giulianini, Franco %A Goddard, William A %A Goel, Anuj %A Gottesman, Omri %A Grove, Megan L %A Gustafsson, Stefan %A Hai, Yang %A Hallmans, Goran %A Heo, Jiyoung %A Hoffmann, Per %A Ikram, Mohammad K %A Jensen, Richard A %A Jørgensen, Marit E %A Jørgensen, Torben %A Karaleftheri, Maria %A Khor, Chiea C %A Kirkpatrick, Andrea %A Kraja, Aldi T %A Kuusisto, Johanna %A Lange, Ethan M %A Lee, I T %A Lee, Wen-Jane %A Leong, Aaron %A Liao, Jiemin %A Liu, Chunyu %A Liu, Yongmei %A Lindgren, Cecilia M %A Linneberg, Allan %A Malerba, Giovanni %A Mamakou, Vasiliki %A Marouli, Eirini %A Maruthur, Nisa M %A Matchan, Angela %A McKean-Cowdin, Roberta %A McLeod, Olga %A Metcalf, Ginger A %A Mohlke, Karen L %A Muzny, Donna M %A Ntalla, Ioanna %A Palmer, Nicholette D %A Pasko, Dorota %A Peter, Andreas %A Rayner, Nigel W %A Renstrom, Frida %A Rice, Ken %A Sala, Cinzia F %A Sennblad, Bengt %A Serafetinidis, Ioannis %A Smith, Jennifer A %A Soranzo, Nicole %A Speliotes, Elizabeth K %A Stahl, Eli A %A Stirrups, Kathleen %A Tentolouris, Nikos %A Thanopoulou, Anastasia %A Torres, Mina %A Traglia, Michela %A Tsafantakis, Emmanouil %A Javad, Sundas %A Yanek, Lisa R %A Zengini, Eleni %A Becker, Diane M %A Bis, Joshua C %A Brown, James B %A Cupples, L Adrienne %A Hansen, Torben %A Ingelsson, Erik %A Karter, Andrew J %A Lorenzo, Carlos %A Mathias, Rasika A %A Norris, Jill M %A Peloso, Gina M %A Sheu, Wayne H-H %A Toniolo, Daniela %A Vaidya, Dhananjay %A Varma, Rohit %A Wagenknecht, Lynne E %A Boeing, Heiner %A Bottinger, Erwin P %A Dedoussis, George %A Deloukas, Panos %A Ferrannini, Ele %A Franco, Oscar H %A Franks, Paul W %A Gibbs, Richard A %A Gudnason, Vilmundur %A Hamsten, Anders %A Harris, Tamara B %A Hattersley, Andrew T %A Hayward, Caroline %A Hofman, Albert %A Jansson, Jan-Håkan %A Langenberg, Claudia %A Launer, Lenore J %A Levy, Daniel %A Oostra, Ben A %A O'Donnell, Christopher J %A O'Rahilly, Stephen %A Padmanabhan, Sandosh %A Pankow, James S %A Polasek, Ozren %A Province, Michael A %A Rich, Stephen S %A Ridker, Paul M %A Rudan, Igor %A Schulze, Matthias B %A Smith, Blair H %A Uitterlinden, André G %A Walker, Mark %A Watkins, Hugh %A Wong, Tien Y %A Zeggini, Eleftheria %A Laakso, Markku %A Borecki, Ingrid B %A Chasman, Daniel I %A Pedersen, Oluf %A Psaty, Bruce M %A Tai, E Shyong %A van Duijn, Cornelia M %A Wareham, Nicholas J %A Waterworth, Dawn M %A Boerwinkle, Eric %A Kao, W H Linda %A Florez, Jose C %A Loos, Ruth J F %A Wilson, James G %A Frayling, Timothy M %A Siscovick, David S %A Dupuis, Josée %A Rotter, Jerome I %A Meigs, James B %A Scott, Robert A %A Goodarzi, Mark O %K Black People %K Blood Glucose %K Diabetes Mellitus, Type 2 %K Exome %K Fasting %K Genetic Association Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Glucagon-Like Peptide-1 Receptor %K Glucose-6-Phosphatase %K Humans %K Insulin %K Mutation Rate %K Oligonucleotide Array Sequence Analysis %K Polymorphism, Single Nucleotide %K White People %X

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

%B Nat Commun %V 6 %P 5897 %8 2015 Jan 29 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/25631608?dopt=Abstract %R 10.1038/ncomms6897