@article {6605, title = {Loss-of-function mutations in APOC3, triglycerides, and coronary disease.}, journal = {N Engl J Med}, volume = {371}, year = {2014}, month = {2014 Jul 3}, pages = {22-31}, abstract = {

BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype.

METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.

RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G{\textrightarrow}A and IVS3+1G{\textrightarrow}T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39\% lower than levels in noncarriers (P<1{\texttimes}10(-20)), and circulating levels of APOC3 in carriers were 46\% lower than levels in noncarriers (P=8{\texttimes}10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40\% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95\% confidence interval, 0.47 to 0.75; P=4{\texttimes}10(-6)).

CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).

}, keywords = {African Continental Ancestry Group, Apolipoprotein C-III, Coronary Disease, European Continental Ancestry Group, Exome, Genotype, Heterozygote, Humans, Liver, Mutation, Risk Factors, Sequence Analysis, DNA, Triglycerides}, issn = {1533-4406}, doi = {10.1056/NEJMoa1307095}, author = {Crosby, Jacy and Peloso, Gina M and Auer, Paul L and Crosslin, David R and Stitziel, Nathan O and Lange, Leslie A and Lu, Yingchang and Tang, Zheng-Zheng and Zhang, He and Hindy, George and Masca, Nicholas and Stirrups, Kathleen and Kanoni, Stavroula and Do, Ron and Jun, Goo and Hu, Youna and Kang, Hyun Min and Xue, Chenyi and Goel, Anuj and Farrall, Martin and Duga, Stefano and Merlini, Pier Angelica and Asselta, Rosanna and Girelli, Domenico and Olivieri, Oliviero and Martinelli, Nicola and Yin, Wu and Reilly, Dermot and Speliotes, Elizabeth and Fox, Caroline S and Hveem, Kristian and Holmen, Oddgeir L and Nikpay, Majid and Farlow, Deborah N and Assimes, Themistocles L and Franceschini, Nora and Robinson, Jennifer and North, Kari E and Martin, Lisa W and DePristo, Mark and Gupta, Namrata and Escher, Stefan A and Jansson, Jan-H{\r a}kan and Van Zuydam, Natalie and Palmer, Colin N A and Wareham, Nicholas and Koch, Werner and Meitinger, Thomas and Peters, Annette and Lieb, Wolfgang and Erbel, Raimund and K{\"o}nig, Inke R and Kruppa, Jochen and Degenhardt, Franziska and Gottesman, Omri and Bottinger, Erwin P and O{\textquoteright}Donnell, Christopher J and Psaty, Bruce M and Ballantyne, Christie M and Abecasis, Goncalo and Ordovas, Jose M and Melander, Olle and Watkins, Hugh and Orho-Melander, Marju and Ardissino, Diego and Loos, Ruth J F and McPherson, Ruth and Willer, Cristen J and Erdmann, Jeanette and Hall, Alistair S and Samani, Nilesh J and Deloukas, Panos and Schunkert, Heribert and Wilson, James G and Kooperberg, Charles and Rich, Stephen S and Tracy, Russell P and Lin, Dan-Yu and Altshuler, David and Gabriel, Stacey and Nickerson, Deborah A and Jarvik, Gail P and Cupples, L Adrienne and Reiner, Alex P and Boerwinkle, Eric and Kathiresan, Sekar} } @article {7010, title = {Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.}, journal = {J Am Coll Cardiol}, volume = {67}, year = {2016}, month = {2016 Jun 7}, pages = {2578-89}, abstract = {

BACKGROUND: Approximately 7\% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol~>=190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by~a~single LDL cholesterol measurement.

OBJECTIVES: This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level.

METHODS: Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database.

RESULTS: Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7\%) had LDL cholesterol >=190~mg/dl; of these, only 24 (1.7\%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol~>=190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95\% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol~>=190 mg/dl and~an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95\% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers.

CONCLUSIONS: Among participants with LDL cholesterol~>=190 mg/dl, gene sequencing identified an FH mutation in~<2\%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.

}, issn = {1558-3597}, doi = {10.1016/j.jacc.2016.03.520}, author = {Khera, Amit V and Won, Hong-Hee and Peloso, Gina M and Lawson, Kim S and Bartz, Traci M and Deng, Xuan and van Leeuwen, Elisabeth M and Natarajan, Pradeep and Emdin, Connor A and Bick, Alexander G and Morrison, Alanna C and Brody, Jennifer A and Gupta, Namrata and Nomura, Akihiro and Kessler, Thorsten and Duga, Stefano and Bis, Joshua C and van Duijn, Cornelia M and Cupples, L Adrienne and Psaty, Bruce and Rader, Daniel J and Danesh, John and Schunkert, Heribert and McPherson, Ruth and Farrall, Martin and Watkins, Hugh and Lander, Eric and Wilson, James G and Correa, Adolfo and Boerwinkle, Eric and Merlini, Piera Angelica and Ardissino, Diego and Saleheen, Danish and Gabriel, Stacey and Kathiresan, Sekar} } @article {7553, title = {Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Oct 27}, pages = {1560-1563}, issn = {1546-1718}, doi = {10.1038/ng.3968}, author = {Brody, Jennifer A and Morrison, Alanna C and Bis, Joshua C and O{\textquoteright}Connell, Jeffrey R and Brown, Michael R and Huffman, Jennifer E and Ames, Darren C and Carroll, Andrew and Conomos, Matthew P and Gabriel, Stacey and Gibbs, Richard A and Gogarten, Stephanie M and Gupta, Namrata and Jaquish, Cashell E and Johnson, Andrew D and Lewis, Joshua P and Liu, Xiaoming and Manning, Alisa K and Papanicolaou, George J and Pitsillides, Achilleas N and Rice, Kenneth M and Salerno, William and Sitlani, Colleen M and Smith, Nicholas L and Heckbert, Susan R and Laurie, Cathy C and Mitchell, Braxton D and Vasan, Ramachandran S and Rich, Stephen S and Rotter, Jerome I and Wilson, James G and Boerwinkle, Eric and Psaty, Bruce M and Cupples, L Adrienne} } @article {7811, title = {Multi-ethnic genome-wide association study for atrial fibrillation.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Sep}, pages = {1225-1233}, abstract = {

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.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0133-9}, author = {Roselli, Carolina and Chaffin, Mark D and Weng, Lu-Chen and Aeschbacher, Stefanie and Ahlberg, Gustav and Albert, Christine M and Almgren, Peter and Alonso, Alvaro and Anderson, Christopher D and Aragam, Krishna G and Arking, Dan E and Barnard, John and Bartz, Traci M and Benjamin, Emelia J and Bihlmeyer, Nathan A and Bis, Joshua C and Bloom, Heather L and Boerwinkle, Eric and Bottinger, Erwin B and Brody, Jennifer A and Calkins, Hugh and Campbell, Archie and Cappola, Thomas P and Carlquist, John and Chasman, Daniel I and Chen, Lin Y and Chen, Yii-Der Ida and Choi, Eue-Keun and Choi, Seung Hoan and Christophersen, Ingrid E and Chung, Mina K and Cole, John W and Conen, David and Cook, James and Crijns, Harry J and Cutler, Michael J and Damrauer, Scott M and Daniels, Brian R and Darbar, Dawood and Delgado, Graciela and Denny, Joshua C and Dichgans, Martin and D{\"o}rr, Marcus and Dudink, Elton A and Dudley, Samuel C and Esa, Nada and Esko, T{\~o}nu and Eskola, Markku and Fatkin, Diane and Felix, Stephan B and Ford, Ian and Franco, Oscar H and Geelhoed, Bastiaan and Grewal, Raji P and Gudnason, Vilmundur and Guo, Xiuqing and Gupta, Namrata and Gustafsson, Stefan and Gutmann, Rebecca and Hamsten, Anders and Harris, Tamara B and Hayward, Caroline and Heckbert, Susan R and Hernesniemi, Jussi and Hocking, Lynne J and Hofman, Albert and Horimoto, Andrea R V R and Huang, Jie and Huang, Paul L and Huffman, Jennifer and Ingelsson, Erik and Ipek, Esra Gucuk and Ito, Kaoru and Jimenez-Conde, Jordi and Johnson, Renee and Jukema, J Wouter and K{\"a}{\"a}b, Stefan and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kane, John P and Kastrati, Adnan and Kathiresan, Sekar and Katschnig-Winter, Petra and Kavousi, Maryam and Kessler, Thorsten and Kietselaer, Bas L and Kirchhof, Paulus and Kleber, Marcus E and Knight, Stacey and Krieger, Jose E and Kubo, Michiaki and Launer, Lenore J and Laurikka, Jari and Lehtim{\"a}ki, Terho and Leineweber, Kirsten and Lemaitre, Rozenn N and Li, Man and Lim, Hong Euy and Lin, Henry J and Lin, Honghuang and Lind, Lars and Lindgren, Cecilia M and Lokki, Marja-Liisa and London, Barry and Loos, Ruth J F and Low, Siew-Kee and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Macfarlane, Peter W and Magnusson, Patrik K and Mahajan, Anubha and Malik, Rainer and Mansur, Alfredo J and Marcus, Gregory M and Margolin, Lauren and Margulies, Kenneth B and M{\"a}rz, Winfried and McManus, David D and Melander, Olle and Mohanty, Sanghamitra and Montgomery, Jay A and Morley, Michael P and Morris, Andrew P and M{\"u}ller-Nurasyid, Martina and Natale, Andrea and Nazarian, Saman and Neumann, Benjamin and Newton-Cheh, Christopher and Niemeijer, Maartje N and Nikus, Kjell and Nilsson, Peter and Noordam, Raymond and Oellers, Heidi and Olesen, Morten S and Orho-Melander, Marju and Padmanabhan, Sandosh and Pak, Hui-Nam and Par{\'e}, Guillaume and Pedersen, Nancy L and Pera, Joanna and Pereira, Alexandre and Porteous, David and Psaty, Bruce M and Pulit, Sara L and Pullinger, Clive R and Rader, Daniel J and Refsgaard, Lena and Ribas{\'e}s, Marta and Ridker, Paul M and Rienstra, Michiel and Risch, Lorenz and Roden, Dan M and Rosand, Jonathan and Rosenberg, Michael A and Rost, Natalia and Rotter, Jerome I and Saba, Samir and Sandhu, Roopinder K and Schnabel, Renate B and Schramm, Katharina and Schunkert, Heribert and Schurman, Claudia and Scott, Stuart A and Sepp{\"a}l{\"a}, Ilkka and Shaffer, Christian and Shah, Svati and Shalaby, Alaa A and Shim, Jaemin and Shoemaker, M Benjamin and Siland, Joylene E and Sinisalo, Juha and Sinner, Moritz F and Slowik, Agnieszka and Smith, Albert V and Smith, Blair H and Smith, J Gustav and Smith, Jonathan D and Smith, Nicholas L and Soliman, Elsayed Z and Sotoodehnia, Nona and Stricker, Bruno H and Sun, Albert and Sun, Han and Svendsen, Jesper H and Tanaka, Toshihiro and Tanriverdi, Kahraman and Taylor, Kent D and Teder-Laving, Maris and Teumer, Alexander and Th{\'e}riault, S{\'e}bastien and Trompet, Stella and Tucker, Nathan R and Tveit, Arnljot and Uitterlinden, Andr{\'e} G and van der Harst, Pim and Van Gelder, Isabelle C and Van Wagoner, David R and Verweij, Niek and Vlachopoulou, Efthymia and V{\"o}lker, Uwe and Wang, Biqi and Weeke, Peter E and Weijs, Bob and Weiss, Raul and Weiss, Stefan and Wells, Quinn S and Wiggins, Kerri L and Wong, Jorge A and Woo, Daniel and Worrall, Bradford B and Yang, Pil-Sung and Yao, Jie and Yoneda, Zachary T and Zeller, Tanja and Zeng, Lingyao and Lubitz, Steven A and Lunetta, Kathryn L and Ellinor, Patrick T} } @article {7785, title = {Whole exome sequencing study identifies novel rare and common Alzheimer{\textquoteright}s-Associated variants involved in immune response and transcriptional regulation.}, journal = {Mol Psychiatry}, year = {2018}, month = {2018 Aug 14}, abstract = {

The Alzheimer{\textquoteright}s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 {\texttimes} 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 {\texttimes} 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 {\texttimes} 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

}, issn = {1476-5578}, doi = {10.1038/s41380-018-0112-7}, author = {Bis, Joshua C and Jian, Xueqiu and Kunkle, Brian W and Chen, Yuning and Hamilton-Nelson, Kara L and Bush, William S and Salerno, William J and Lancour, Daniel and Ma, Yiyi and Renton, Alan E and Marcora, Edoardo and Farrell, John J and Zhao, Yi and Qu, Liming and Ahmad, Shahzad and Amin, Najaf and Amouyel, Philippe and Beecham, Gary W and Below, Jennifer E and Campion, Dominique and Charbonnier, Camille and Chung, Jaeyoon and Crane, Paul K and Cruchaga, Carlos and Cupples, L Adrienne and Dartigues, Jean-Fran{\c c}ois and Debette, Stephanie and Deleuze, Jean-Francois and Fulton, Lucinda and Gabriel, Stacey B and Genin, Emmanuelle and Gibbs, Richard A and Goate, Alison and Grenier-Boley, Benjamin and Gupta, Namrata and Haines, Jonathan L and Havulinna, Aki S and Helisalmi, Seppo and Hiltunen, Mikko and Howrigan, Daniel P and Ikram, M Arfan and Kaprio, Jaakko and Konrad, Jan and Kuzma, Amanda and Lander, Eric S and Lathrop, Mark and Lehtim{\"a}ki, Terho and Lin, Honghuang and Mattila, Kari and Mayeux, Richard and Muzny, Donna M and Nasser, Waleed and Neale, Benjamin and Nho, Kwangsik and Nicolas, Ga{\"e}l and Patel, Devanshi and Pericak-Vance, Margaret A and Perola, Markus and Psaty, Bruce M and Quenez, Olivier and Rajabli, Farid and Redon, Richard and Reitz, Christiane and Remes, Anne M and Salomaa, Veikko and Sarnowski, Chloe and Schmidt, Helena and Schmidt, Michael and Schmidt, Reinhold and Soininen, Hilkka and Thornton, Timothy A and Tosto, Giuseppe and Tzourio, Christophe and van der Lee, Sven J and van Duijn, Cornelia M and Vardarajan, Badri and Wang, Weixin and Wijsman, Ellen and Wilson, Richard K and Witten, Daniela and Worley, Kim C and Zhang, Xiaoling and Bellenguez, C{\'e}line and Lambert, Jean-Charles and Kurki, Mitja I and Palotie, Aarno and Daly, Mark and Boerwinkle, Eric and Lunetta, Kathryn L and DeStefano, Anita L and Dupuis, Jos{\'e}e and Martin, Eden R and Schellenberg, Gerard D and Seshadri, Sudha and Naj, Adam C and Fornage, Myriam and Farrer, Lindsay A} } @article {8639, title = {Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 10 14}, pages = {5182}, abstract = {

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

}, keywords = {Adult, African Americans, Aged, Aged, 80 and over, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Calcium-Binding Proteins, Feasibility Studies, Female, Follow-Up Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Lung, Male, Middle Aged, Polymorphism, Single Nucleotide, Protein Inhibitors of Activated STAT, Pulmonary Disease, Chronic Obstructive, Respiratory Physiological Phenomena, Small Ubiquitin-Related Modifier Proteins, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-020-18334-7}, author = {Zhao, Xutong and Qiao, Dandi and Yang, Chaojie and Kasela, Silva and Kim, Wonji and Ma, Yanlin and Shrine, Nick and Batini, Chiara and Sofer, Tamar and Taliun, Sarah A Gagliano and Sakornsakolpat, Phuwanat and Balte, Pallavi P and Prokopenko, Dmitry and Yu, Bing and Lange, Leslie A and Dupuis, Jos{\'e}e and Cade, Brian E and Lee, Jiwon and Gharib, Sina A and Daya, Michelle and Laurie, Cecelia A and Ruczinski, Ingo and Cupples, L Adrienne and Loehr, Laura R and Bartz, Traci M and Morrison, Alanna C and Psaty, Bruce M and Vasan, Ramachandran S and Wilson, James G and Taylor, Kent D and Durda, Peter and Johnson, W Craig and Cornell, Elaine and Guo, Xiuqing and Liu, Yongmei and Tracy, Russell P and Ardlie, Kristin G and Aguet, Francois and VanDenBerg, David J and Papanicolaou, George J and Rotter, Jerome I and Barnes, Kathleen C and Jain, Deepti and Nickerson, Deborah A and Muzny, Donna M and Metcalf, Ginger A and Doddapaneni, Harshavardhan and Dugan-Perez, Shannon and Gupta, Namrata and Gabriel, Stacey and Rich, Stephen S and O{\textquoteright}Connor, George T and Redline, Susan and Reed, Robert M and Laurie, Cathy C and Daviglus, Martha L and Preudhomme, Liana K and Burkart, Kristin M and Kaplan, Robert C and Wain, Louise V and Tobin, Martin D and London, Stephanie J and Lappalainen, Tuuli and Oelsner, Elizabeth C and Abecasis, Goncalo R and Silverman, Edwin K and Barr, R Graham and Cho, Michael H and Manichaikul, Ani} } @article {9167, title = {Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 08 30}, pages = {5106}, abstract = {

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of >= 0.5 times the endophenotype standard deviation nominates up to 35\% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

}, keywords = {Disease Susceptibility, Endophenotypes, Humans, Long QT Syndrome, Virulence}, issn = {2041-1723}, doi = {10.1038/s41467-022-32009-5}, author = {Halford, Jennifer L and Morrill, Valerie N and Choi, Seung Hoan and Jurgens, Sean J and Melloni, Giorgio and Marston, Nicholas A and Weng, Lu-Chen and Nauffal, Victor and Hall, Amelia W and Gunn, Sophia and Austin-Tse, Christina A and Pirruccello, James P and Khurshid, Shaan and Rehm, Heidi L and Benjamin, Emelia J and Boerwinkle, Eric and Brody, Jennifer A and Correa, Adolfo and Fornwalt, Brandon K and Gupta, Namrata and Haggerty, Christopher M and Harris, Stephanie and Heckbert, Susan R and Hong, Charles C and Kooperberg, Charles and Lin, Henry J and Loos, Ruth J F and Mitchell, Braxton D and Morrison, Alanna C and Post, Wendy and Psaty, Bruce M and Redline, Susan and Rice, Kenneth M and Rich, Stephen S and Rotter, Jerome I and Schnatz, Peter F and Soliman, Elsayed Z and Sotoodehnia, Nona and Wong, Eugene K and Sabatine, Marc S and Ruff, Christian T and Lunetta, Kathryn L and Ellinor, Patrick T and Lubitz, Steven A} } @article {9038, title = {Monogenic and Polygenic Contributions to QTc Prolongation in the Population.}, journal = {Circulation}, year = {2022}, month = {2022 Apr 07}, abstract = {

Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variation to the QT interval in the population. We performed a genome wide association study (GWAS) of the QTc in 84,630 United Kingdom Biobank (UKB) participants and created a polygenic risk score (PRS). Among 26,976 participants with whole genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Fifty-four independent loci were identified by GWAS in the UKB. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS comprising 1,110,494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/ = 1.4 ms, 95\% CI 1.3 -1.5; p-value=1.1{\texttimes}10). Carriers of putative pathogenic rare variants had longer QTc than non-carriers (ΔQTc=10.9 ms [7.4-14.4]). 23.7\% of individuals with QTc>480 ms carried either a monogenic rare variant or had a PRS in the top decile (3.4\% monogenic, 21\% top decile of PRS). QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.121.057261}, author = {Nauffal, Victor and Morrill, Valerie N and Jurgens, Sean J and Choi, Seung Hoan and Hall, Amelia W and Weng, Lu-Chen and Halford, Jennifer L and Austin-Tse, Christina and Haggerty, Christopher M and Harris, Stephanie L and Wong, Eugene K and Alonso, Alvaro and Arking, Dan E and Benjamin, Emelia J and Boerwinkle, Eric and Min, Yuan-I and Correa, Adolfo and Fornwalt, Brandon K and Heckbert, Susan R and Kooperberg, Charles and Lin, Henry J and Loos, Ruth J F and Rice, Kenneth M and Gupta, Namrata and Blackwell, Thomas W and Mitchell, Braxton D and Morrison, Alanna C and Psaty, Bruce M and Post, Wendy S and Redline, Susan and Rehm, Heidi L and Rich, Stephen S and Rotter, Jerome I and Soliman, Elsayed Z and Sotoodehnia, Nona and Lunetta, Kathryn L and Ellinor, Patrick T and Lubitz, Steven A} } @article {9037, title = {Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program.}, journal = {Am J Hum Genet}, year = {2022}, month = {2022 Mar 31}, abstract = {

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

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2022.03.007}, author = {Hu, Xiaowei and Qiao, Dandi and Kim, Wonji and Moll, Matthew and Balte, Pallavi P and Lange, Leslie A and Bartz, Traci M and Kumar, Rajesh and Li, Xingnan and Yu, Bing and Cade, Brian E and Laurie, Cecelia A and Sofer, Tamar and Ruczinski, Ingo and Nickerson, Deborah A and Muzny, Donna M and Metcalf, Ginger A and Doddapaneni, Harshavardhan and Gabriel, Stacy and Gupta, Namrata and Dugan-Perez, Shannon and Cupples, L Adrienne and Loehr, Laura R and Jain, Deepti and Rotter, Jerome I and Wilson, James G and Psaty, Bruce M and Fornage, Myriam and Morrison, Alanna C and Vasan, Ramachandran S and Washko, George and Rich, Stephen S and O{\textquoteright}Connor, George T and Bleecker, Eugene and Kaplan, Robert C and Kalhan, Ravi and Redline, Susan and Gharib, Sina A and Meyers, Deborah and Ortega, Victor and Dupuis, Jos{\'e}e and London, Stephanie J and Lappalainen, Tuuli and Oelsner, Elizabeth C and Silverman, Edwin K and Barr, R Graham and Thornton, Timothy A and Wheeler, Heather E and Cho, Michael H and Im, Hae Kyung and Manichaikul, Ani} } @article {8975, title = {Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.}, journal = {Am J Hum Genet}, volume = {109}, year = {2022}, month = {2022 01 06}, pages = {81-96}, abstract = {

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

}, keywords = {Alleles, Blood Glucose, Case-Control Studies, Computational Biology, Databases, Genetic, Diabetes Mellitus, Type 2, Exome, Genetic Predisposition to Disease, Genetic Variation, Genetics, Population, Genome-Wide Association Study, Humans, Lipid Metabolism, Lipids, Liver, Molecular Sequence Annotation, Multifactorial Inheritance, Open Reading Frames, Phenotype, Polymorphism, Single Nucleotide}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.11.021}, author = {Hindy, George and Dornbos, Peter and Chaffin, Mark D and Liu, Dajiang J and Wang, Minxian and Selvaraj, Margaret Sunitha and Zhang, David and Park, Joseph and Aguilar-Salinas, Carlos A and Antonacci-Fulton, Lucinda and Ardissino, Diego and Arnett, Donna K and Aslibekyan, Stella and Atzmon, Gil and Ballantyne, Christie M and Barajas-Olmos, Francisco and Barzilai, Nir and Becker, Lewis C and Bielak, Lawrence F and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bonnycastle, Lori L and Bottinger, Erwin and Bowden, Donald W and Bown, Matthew J and Brody, Jennifer A and Broome, Jai G and Burtt, Noel P and Cade, Brian E and Centeno-Cruz, Federico and Chan, Edmund and Chang, Yi-Cheng and Chen, Yii-der I and Cheng, Ching-Yu and Choi, Won Jung and Chowdhury, Rajiv and Contreras-Cubas, Cecilia and C{\'o}rdova, Emilio J and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and Danesh, John and de Vries, Paul S and DeFronzo, Ralph A and Doddapaneni, Harsha and Duggirala, Ravindranath and Dutcher, Susan K and Ellinor, Patrick T and Emery, Leslie S and Florez, Jose C and Fornage, Myriam and Freedman, Barry I and Fuster, Valentin and Garay-Sevilla, Ma Eugenia and Garc{\'\i}a-Ortiz, Humberto and Germer, Soren and Gibbs, Richard A and Gieger, Christian and Glaser, Benjamin and Gonzalez, Clicerio and Gonzalez-Villalpando, Maria Elena and Graff, Mariaelisa and Graham, Sarah E and Grarup, Niels and Groop, Leif C and Guo, Xiuqing and Gupta, Namrata and Han, Sohee and Hanis, Craig L and Hansen, Torben and He, Jiang and Heard-Costa, Nancy L and Hung, Yi-Jen and Hwang, Mi Yeong and Irvin, Marguerite R and Islas-Andrade, Sergio and Jarvik, Gail P and Kang, Hyun Min and Kardia, Sharon L R and Kelly, Tanika and Kenny, Eimear E and Khan, Alyna T and Kim, Bong-Jo and Kim, Ryan W and Kim, Young Jin and Koistinen, Heikki A and Kooperberg, Charles and Kuusisto, Johanna and Kwak, Soo Heon and Laakso, Markku and Lange, Leslie A and Lee, Jiwon and Lee, Juyoung and Lee, Seonwook and Lehman, Donna M and Lemaitre, Rozenn N and Linneberg, Allan and Liu, Jianjun and Loos, Ruth J F and Lubitz, Steven A and Lyssenko, Valeriya and Ma, Ronald C W and Martin, Lisa Warsinger and Mart{\'\i}nez-Hern{\'a}ndez, Ang{\'e}lica and Mathias, Rasika A and McGarvey, Stephen T and McPherson, Ruth and Meigs, James B and Meitinger, Thomas and Melander, Olle and Mendoza-Caamal, Elvia and Metcalf, Ginger A and Mi, Xuenan and Mohlke, Karen L and Montasser, May E and Moon, Jee-Young and Moreno-Macias, Hortensia and Morrison, Alanna C and Muzny, Donna M and Nelson, Sarah C and Nilsson, Peter M and O{\textquoteright}Connell, Jeffrey R and Orho-Melander, Marju and Orozco, Lorena and Palmer, Colin N A and Palmer, Nicholette D and Park, Cheol Joo and Park, Kyong Soo and Pedersen, Oluf and Peralta, Juan M and Peyser, Patricia A and Post, Wendy S and Preuss, Michael and Psaty, Bruce M and Qi, Qibin and Rao, D C and Redline, Susan and Reiner, Alexander P and Revilla-Monsalve, Cristina and Rich, Stephen S and Samani, Nilesh and Schunkert, Heribert and Schurmann, Claudia and Seo, Daekwan and Seo, Jeong-Sun and Sim, Xueling and Sladek, Rob and Small, Kerrin S and So, Wing Yee and Stilp, Adrienne M and Tai, E Shyong and Tam, Claudia H T and Taylor, Kent D and Teo, Yik Ying and Thameem, Farook and Tomlinson, Brian and Tsai, Michael Y and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and van Dam, Rob M and Vasan, Ramachandran S and Viaud Martinez, Karine A and Wang, Fei Fei and Wang, Xuzhi and Watkins, Hugh and Weeks, Daniel E and Wilson, James G and Witte, Daniel R and Wong, Tien-Yin and Yanek, Lisa R and Kathiresan, Sekar and Rader, Daniel J and Rotter, Jerome I and Boehnke, Michael and McCarthy, Mark I and Willer, Cristen J and Natarajan, Pradeep and Flannick, Jason A and Khera, Amit V and Peloso, Gina M} } @article {9537, title = {Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.}, journal = {Circ Genom Precis Med}, year = {2023}, month = {2023 Nov 28}, pages = {e004176}, abstract = {

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test.

RESULTS: Using a Bonferroni-corrected significance threshold of <1.6{\texttimes}10, we identified 3 genes (, , and ) associated with CAC and 2 genes ( and ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both and also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis.

CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.123.004176}, author = {Hasbani, Natalie R and Westerman, Kenneth E and Heon Kwak, Soo and Chen, Han and Li, Xihao and DiCorpo, Daniel and Wessel, Jennifer and Bis, Joshua C and Sarnowski, Chloe and Wu, Peitao and Bielak, Lawrence F and Guo, Xiuqing and Heard-Costa, Nancy and Kinney, Gregory and Mahaney, Michael C and Montasser, May E and Palmer, Nicholette D and Raffield, Laura M and Terry, James G and Yanek, Lisa R and Bon, Jessica and Bowden, Donald W and Brody, Jennifer A and Duggirala, Ravindranath and Jacobs, David R and Kalyani, Rita R and Lange, Leslie A and Mitchell, Braxton D and Smith, Jennifer A and Taylor, Kent D and Carson, April and Curran, Joanne E and Fornage, Myriam and Freedman, Barry I and Gabriel, Stacey and Gibbs, Richard A and Gupta, Namrata and Kardia, Sharon L R and Kral, Brian G and Momin, Zeineen and Newman, Anne B and Post, Wendy S and Viaud-Martinez, Karine A and Young, Kendra A and Becker, Lewis C and Bertoni, Alain and Blangero, John and Carr, John J and Pratte, Katherine and Psaty, Bruce M and Rich, Stephen S and Wu, Joseph C and Malhotra, Rajeev and Peyser, Patricia A and Morrison, Alanna C and Vasan, Ramachandran S and Lin, Xihong and Rotter, Jerome I and Meigs, James B and Manning, Alisa K and de Vries, Paul S} } @article {9321, title = {Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program.}, journal = {Circ Genom Precis Med}, year = {2023}, month = {2023 Mar 24}, pages = {e003532}, abstract = {

Background Risk for venous thromboembolism has a strong genetic component. Whole genome sequencingfrom the Trans-Omics for Precision Medicine program allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. Methods The 3793 cases and 7834 controls (11.6\% of cases were Black, Hispanic/Latino, or Asian American) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). Results Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only (odds ratio, 6.2 for carriers of rare variants; =7.4{\texttimes}10) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at (odds ratio, 3.8; =1.6{\texttimes}10), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: became significant (minimum =1.8{\texttimes}10 with the secondary filter), while did not (minimum =4.4{\texttimes}10 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, , became significant (=4.4{\texttimes}10 using all missense variants with minor allele frequency <0.0005). Conclusions Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel locus and to identify additional rare variation associated with venous thromboembolism.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.121.003532}, author = {Seyerle, Amanda A and Laurie, Cecelia A and Coombes, Brandon J and Jain, Deepti and Conomos, Matthew P and Brody, Jennifer and Chen, Ming-Huei and Gogarten, Stephanie M and Beutel, Kathleen M and Gupta, Namrata and Heckbert, Susan R and Jackson, Rebecca D and Johnson, Andrew D and Ko, Darae and Manson, JoAnn E and McKnight, Barbara and Metcalf, Ginger A and Morrison, Alanna C and Reiner, Alexander P and Sofer, Tamar and Tang, Weihong and Wiggins, Kerri L and Boerwinkle, Eric and Andrade, Mariza de and Gabriel, Stacey B and Gibbs, Richard A and Laurie, Cathy C and Psaty, Bruce M and Vasan, Ramachandran S and Rice, Ken and Kooperberg, Charles and Pankow, James S and Smith, Nicholas L and Pankratz, Nathan} } @article {9907, title = {Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.}, journal = {Nat Genet}, volume = {57}, year = {2025}, month = {2025 Mar}, pages = {548-562}, abstract = {

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.

}, keywords = {Atrial Fibrillation, Case-Control Studies, Exome Sequencing, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Myocytes, Cardiac, Risk Factors}, issn = {1546-1718}, doi = {10.1038/s41588-025-02074-9}, author = {Choi, Seung Hoan and Jurgens, Sean J and Xiao, Ling and Hill, Matthew C and Haggerty, Christopher M and Sveinbj{\"o}rnsson, Gar{\dh}ar and Morrill, Valerie N and Marston, Nicholas A and Weng, Lu-Chen and Pirruccello, James P and Arnar, David O and Gudbjartsson, Daniel Fannar and Mantineo, Helene and von Falkenhausen, Aenne S and Natale, Andrea and Tveit, Arnljot and Geelhoed, Bastiaan and Roselli, Carolina and Van Wagoner, David R and Darbar, Dawood and Haase, Doreen and Soliman, Elsayed Z and Davogustto, Giovanni E and Jun, Goo and Calkins, Hugh and Anderson, Jeffrey L and Brody, Jennifer A and Halford, Jennifer L and Barnard, John and Hokanson, John E and Smith, Jonathan D and Bis, Joshua C and Young, Kendra and Johnson, Linda S B and Risch, Lorenz and Gula, Lorne J and Kwee, Lydia Coulter and Chaffin, Mark D and K{\"u}hne, Michael and Preuss, Michael and Gupta, Namrata and Nafissi, Navid A and Smith, Nicholas L and Nilsson, Peter M and van der Harst, Pim and Wells, Quinn S and Judy, Renae L and Schnabel, Renate B and Johnson, Renee and Smit, Roelof A J and Gabriel, Stacey and Knight, Stacey and Furukawa, Tetsushi and Blackwell, Thomas W and Nauffal, Victor and Wang, Xin and Min, Yuan-I and Yoneda, Zachary T and Laksman, Zachary W M and Bezzina, Connie R and Alonso, Alvaro and Psaty, Bruce M and Albert, Christine M and Arking, Dan E and Roden, Dan M and Chasman, Daniel I and Rader, Daniel J and Conen, David and McManus, David D and Fatkin, Diane and Benjamin, Emelia J and Boerwinkle, Eric and Marcus, Gregory M and Christophersen, Ingrid E and Smith, J Gustav and Roberts, Jason D and Raffield, Laura M and Shoemaker, M Benjamin and Cho, Michael H and Cutler, Michael J and Rienstra, Michiel and Chung, Mina K and S Olesen, Morten and Sinner, Moritz F and Sotoodehnia, Nona and Kirchhof, Paulus and Loos, Ruth J F and Nazarian, Saman and Mohanty, Sanghamitra and Damrauer, Scott M and K{\"a}{\"a}b, Stefan and Heckbert, Susan R and Redline, Susan and Shah, Svati H and Tanaka, Toshihiro and Ebana, Yusuke and Holm, Hilma and Stefansson, Kari and Ruff, Christian T and Sabatine, Marc S and Lunetta, Kathryn L and Lubitz, Steven A and Ellinor, Patrick T} }