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Weng, Lu-Chen

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Weng

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Lu-Chen

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Weng, Lu-Chen
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    Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium
    (Nature Publishing Group UK, 2017) Weng, Lu-Chen; Lunetta, Kathryn L.; Müller-Nurasyid, Martina; Smith, Albert Vernon; Thériault, Sébastien; Weeke, Peter E.; Barnard, John; Bis, Joshua C.; Lyytikäinen, Leo-Pekka; Kleber, Marcus E.; Martinsson, Andreas; Lin, Henry J.; Rienstra, Michiel; Trompet, Stella; Krijthe, Bouwe P.; Dörr, Marcus; Klarin, Derek; Chasman, Daniel; Sinner, Moritz F.; Waldenberger, Melanie; Launer, Lenore J.; Harris, Tamara B.; Soliman, Elsayed Z.; Alonso, Alvaro; Paré, Guillaume; Teixeira, Pedro L.; Denny, Joshua C.; Shoemaker, M. Benjamin; Van Wagoner, David R.; Smith, Jonathan D.; Psaty, Bruce M.; Sotoodehnia, Nona; Taylor, Kent D.; Kähönen, Mika; Nikus, Kjell; Delgado, Graciela E.; Melander, Olle; Engström, Gunnar; Yao, Jie; Guo, Xiuqing; Christophersen, Ingrid E.; Ellinor, Patrick; Geelhoed, Bastiaan; Verweij, Niek; Macfarlane, Peter; Ford, Ian; Heeringa, Jan; Franco, Oscar H.; Uitterlinden, André G.; Völker, Uwe; Teumer, Alexander; Rose, Lynda M.; Kääb, Stefan; Gudnason, Vilmundur; Arking, Dan E.; Conen, David; Roden, Dan M.; Chung, Mina K.; Heckbert, Susan R.; Benjamin, Emelia J.; Lehtimäki, Terho; März, Winfried; Smith, J. Gustav; Rotter, Jerome I.; van der Harst, Pim; Jukema, J. Wouter; Stricker, Bruno H.; Felix, Stephan B.; Albert, Christine; Lubitz, Steven
    It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10−5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10−8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.
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    Whole Exome Sequencing in Atrial Fibrillation
    (Public Library of Science, 2016) Lubitz, Steven; Brody, Jennifer A.; Bihlmeyer, Nathan A.; Roselli, Carolina; Weng, Lu-Chen; Christophersen, Ingrid E.; Alonso, Alvaro; Boerwinkle, Eric; Gibbs, Richard A.; Bis, Joshua C.; Cupples, L. Adrienne; Mohler, Peter J.; Nickerson, Deborah A.; Muzny, Donna; Perez, Marco V.; Psaty, Bruce M.; Soliman, Elsayed Z.; Sotoodehnia, Nona; Lunetta, Kathryn L.; Benjamin, Emelia J.; Heckbert, Susan R.; Arking, Dan E.; Ellinor, Patrick; Lin, Honghuang
    Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13–1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.