TY - JOUR T1 - Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval. JF - Pharmacogenomics J Y1 - 2014 A1 - Avery, C L A1 - Sitlani, C M A1 - Arking, D E A1 - Arnett, D K A1 - Bis, J C A1 - Boerwinkle, E A1 - Buckley, B M A1 - Ida Chen, Y-D A1 - de Craen, A J M A1 - Eijgelsheim, M A1 - Enquobahrie, D A1 - Evans, D S A1 - Ford, I A1 - Garcia, M E A1 - Gudnason, V A1 - Harris, T B A1 - Heckbert, S R A1 - Hochner, H A1 - Hofman, A A1 - Hsueh, W-C A1 - Isaacs, A A1 - Jukema, J W A1 - Knekt, P A1 - Kors, J A A1 - Krijthe, B P A1 - Kristiansson, K A1 - Laaksonen, M A1 - Liu, Y A1 - Li, X A1 - Macfarlane, P W A1 - Newton-Cheh, C A1 - Nieminen, M S A1 - Oostra, B A A1 - Peloso, G M A1 - Porthan, K A1 - Rice, K A1 - Rivadeneira, F F A1 - Rotter, J I A1 - Salomaa, V A1 - Sattar, N A1 - Siscovick, D S A1 - Slagboom, P E A1 - Smith, A V A1 - Sotoodehnia, N A1 - Stott, D J A1 - Stricker, B H A1 - Stürmer, T A1 - Trompet, S A1 - Uitterlinden, A G A1 - van Duijn, C A1 - Westendorp, R G J A1 - Witteman, J C A1 - Whitsel, E A A1 - Psaty, B M KW - Computer Simulation KW - Cross-Sectional Studies KW - Drug-Related Side Effects and Adverse Reactions KW - Electrocardiography KW - European Continental Ancestry Group KW - Gene-Environment Interaction KW - Genome-Wide Association Study KW - Humans KW - Linear Models KW - Long QT Syndrome KW - Markov Chains KW - Pharmacogenetics KW - Polymorphism, Single Nucleotide KW - Quantitative Trait, Heritable AB -

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

VL - 14 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23459443?dopt=Abstract ER - TY - JOUR T1 - Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). JF - Mol Psychiatry Y1 - 2015 A1 - Davies, G A1 - Armstrong, N A1 - Bis, J C A1 - Bressler, J A1 - Chouraki, V A1 - Giddaluru, S A1 - Hofer, E A1 - Ibrahim-Verbaas, C A A1 - Kirin, M A1 - Lahti, J A1 - van der Lee, S J A1 - Le Hellard, S A1 - Liu, T A1 - Marioni, R E A1 - Oldmeadow, C A1 - Postmus, I A1 - Smith, A V A1 - Smith, J A A1 - Thalamuthu, A A1 - Thomson, R A1 - Vitart, V A1 - Wang, J A1 - Yu, L A1 - Zgaga, L A1 - Zhao, W A1 - Boxall, R A1 - Harris, S E A1 - Hill, W D A1 - Liewald, D C A1 - Luciano, M A1 - Adams, H A1 - Ames, D A1 - Amin, N A1 - Amouyel, P A1 - Assareh, A A A1 - Au, R A1 - Becker, J T A1 - Beiser, A A1 - Berr, C A1 - Bertram, L A1 - Boerwinkle, E A1 - Buckley, B M A1 - Campbell, H A1 - Corley, J A1 - De Jager, P L A1 - Dufouil, C A1 - Eriksson, J G A1 - Espeseth, T A1 - Faul, J D A1 - Ford, I A1 - Gottesman, R F A1 - Griswold, M E A1 - Gudnason, V A1 - Harris, T B A1 - Heiss, G A1 - Hofman, A A1 - Holliday, E G A1 - Huffman, J A1 - Kardia, S L R A1 - Kochan, N A1 - Knopman, D S A1 - Kwok, J B A1 - Lambert, J-C A1 - Lee, T A1 - Li, G A1 - Li, S-C A1 - Loitfelder, M A1 - Lopez, O L A1 - Lundervold, A J A1 - Lundqvist, A A1 - Mather, K A A1 - Mirza, S S A1 - Nyberg, L A1 - Oostra, B A A1 - Palotie, A A1 - Papenberg, G A1 - Pattie, A A1 - Petrovic, K A1 - Polasek, O A1 - Psaty, B M A1 - Redmond, P A1 - Reppermund, S A1 - Rotter, J I A1 - Schmidt, H A1 - Schuur, M A1 - Schofield, P W A1 - Scott, R J A1 - Steen, V M A1 - Stott, D J A1 - van Swieten, J C A1 - Taylor, K D A1 - Trollor, J A1 - Trompet, S A1 - Uitterlinden, A G A1 - Weinstein, G A1 - Widen, E A1 - Windham, B G A1 - Jukema, J W A1 - Wright, A F A1 - Wright, M J A1 - Yang, Q A1 - Amieva, H A1 - Attia, J R A1 - Bennett, D A A1 - Brodaty, H A1 - de Craen, A J M A1 - Hayward, C A1 - Ikram, M A A1 - Lindenberger, U A1 - Nilsson, L-G A1 - Porteous, D J A1 - Räikkönen, K A1 - Reinvang, I A1 - Rudan, I A1 - Sachdev, P S A1 - Schmidt, R A1 - Schofield, P R A1 - Srikanth, V A1 - Starr, J M A1 - Turner, S T A1 - Weir, D R A1 - Wilson, J F A1 - van Duijn, C A1 - Launer, L A1 - Fitzpatrick, A L A1 - Seshadri, S A1 - Mosley, T H A1 - Deary, I J KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Cognition KW - Cognition Disorders KW - Cohort Studies KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - HMGN1 Protein KW - Humans KW - Male KW - Middle Aged KW - Neuropsychological Tests KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Scotland AB -

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

VL - 20 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25644384?dopt=Abstract ER - TY - JOUR T1 - GWAS for executive function and processing speed suggests involvement of the CADM2 gene. JF - Mol Psychiatry Y1 - 2016 A1 - Ibrahim-Verbaas, C A A1 - Bressler, J A1 - Debette, S A1 - Schuur, M A1 - Smith, A V A1 - Bis, J C A1 - Davies, G A1 - Trompet, S A1 - Smith, J A A1 - Wolf, C A1 - Chibnik, L B A1 - Liu, Y A1 - Vitart, V A1 - Kirin, M A1 - Petrovic, K A1 - Polasek, O A1 - Zgaga, L A1 - Fawns-Ritchie, C A1 - Hoffmann, P A1 - Karjalainen, J A1 - Lahti, J A1 - Llewellyn, D J A1 - Schmidt, C O A1 - Mather, K A A1 - Chouraki, V A1 - Sun, Q A1 - Resnick, S M A1 - Rose, L M A1 - Oldmeadow, C A1 - Stewart, M A1 - Smith, B H A1 - Gudnason, V A1 - Yang, Q A1 - Mirza, S S A1 - Jukema, J W A1 - deJager, P L A1 - Harris, T B A1 - Liewald, D C A1 - Amin, N A1 - Coker, L H A1 - Stegle, O A1 - Lopez, O L A1 - Schmidt, R A1 - Teumer, A A1 - Ford, I A1 - Karbalai, N A1 - Becker, J T A1 - Jonsdottir, M K A1 - Au, R A1 - Fehrmann, R S N A1 - Herms, S A1 - Nalls, M A1 - Zhao, W A1 - Turner, S T A1 - Yaffe, K A1 - Lohman, K A1 - van Swieten, J C A1 - Kardia, S L R A1 - Knopman, D S A1 - Meeks, W M A1 - Heiss, G A1 - Holliday, E G A1 - Schofield, P W A1 - Tanaka, T A1 - Stott, D J A1 - Wang, J A1 - Ridker, P A1 - Gow, A J A1 - Pattie, A A1 - Starr, J M A1 - Hocking, L J A1 - Armstrong, N J A1 - McLachlan, S A1 - Shulman, J M A1 - Pilling, L C A1 - Eiriksdottir, G A1 - Scott, R J A1 - Kochan, N A A1 - Palotie, A A1 - Hsieh, Y-C A1 - Eriksson, J G A1 - Penman, A A1 - Gottesman, R F A1 - Oostra, B A A1 - Yu, L A1 - DeStefano, A L A1 - Beiser, A A1 - Garcia, M A1 - Rotter, J I A1 - Nöthen, M M A1 - Hofman, A A1 - Slagboom, P E A1 - Westendorp, R G J A1 - Buckley, B M A1 - Wolf, P A A1 - Uitterlinden, A G A1 - Psaty, B M A1 - Grabe, H J A1 - Bandinelli, S A1 - Chasman, D I A1 - Grodstein, F A1 - Räikkönen, K A1 - Lambert, J-C A1 - Porteous, D J A1 - Price, J F A1 - Sachdev, P S A1 - Ferrucci, L A1 - Attia, J R A1 - Rudan, I A1 - Hayward, C A1 - Wright, A F A1 - Wilson, J F A1 - Cichon, S A1 - Franke, L A1 - Schmidt, H A1 - Ding, J A1 - de Craen, A J M A1 - Fornage, M A1 - Bennett, D A A1 - Deary, I J A1 - Ikram, M A A1 - Launer, L J A1 - Fitzpatrick, A L A1 - Seshadri, S A1 - van Duijn, C M A1 - Mosley, T H AB -

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

VL - 21 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25869804?dopt=Abstract ER - TY - JOUR T1 - Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group. JF - Pharmacogenomics J Y1 - 2016 A1 - Floyd, J S A1 - Sitlani, C M A1 - Avery, C L A1 - Noordam, R A1 - Li, X A1 - Smith, A V A1 - Gogarten, S M A1 - Li, J A1 - Broer, L A1 - Evans, D S A1 - Trompet, S A1 - Brody, J A A1 - Stewart, J D A1 - Eicher, J D A1 - Seyerle, A A A1 - Roach, J A1 - Lange, L A A1 - Lin, H J A1 - Kors, J A A1 - Harris, T B A1 - Li-Gao, R A1 - Sattar, N A1 - Cummings, S R A1 - Wiggins, K L A1 - Napier, M D A1 - Stürmer, T A1 - Bis, J C A1 - Kerr, K F A1 - Uitterlinden, A G A1 - Taylor, K D A1 - Stott, D J A1 - de Mutsert, R A1 - Launer, L J A1 - Busch, E L A1 - Méndez-Giráldez, R A1 - Sotoodehnia, N A1 - Soliman, E Z A1 - Li, Y A1 - Duan, Q A1 - Rosendaal, F R A1 - Slagboom, P E A1 - Wilhelmsen, K C A1 - Reiner, A P A1 - Chen, Y-DI A1 - Heckbert, S R A1 - Kaplan, R C A1 - Rice, K M A1 - Jukema, J W A1 - Johnson, A D A1 - Liu, Y A1 - Mook-Kanamori, D O A1 - Gudnason, V A1 - Wilson, J G A1 - Rotter, J I A1 - Laurie, C C A1 - Psaty, B M A1 - Whitsel, E A A1 - Cupples, L A A1 - Stricker, B H AB -

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10(-8)), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.The Pharmacogenomics Journal advance online publication, 13 December 2016; doi:10.1038/tpj.2016.90.

ER - TY - JOUR T1 - Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology. JF - Pharmacogenomics J Y1 - 2017 A1 - Seyerle, A A A1 - Sitlani, C M A1 - Noordam, R A1 - Gogarten, S M A1 - Li, J A1 - Li, X A1 - Evans, D S A1 - Sun, F A1 - Laaksonen, M A A1 - Isaacs, A A1 - Kristiansson, K A1 - Highland, H M A1 - Stewart, J D A1 - Harris, T B A1 - Trompet, S A1 - Bis, J C A1 - Peloso, G M A1 - Brody, J A A1 - Broer, L A1 - Busch, E L A1 - Duan, Q A1 - Stilp, A M A1 - O'Donnell, C J A1 - Macfarlane, P W A1 - Floyd, J S A1 - Kors, J A A1 - Lin, H J A1 - Li-Gao, R A1 - Sofer, T A1 - Méndez-Giráldez, R A1 - Cummings, S R A1 - Heckbert, S R A1 - Hofman, A A1 - Ford, I A1 - Li, Y A1 - Launer, L J A1 - Porthan, K A1 - Newton-Cheh, C A1 - Napier, M D A1 - Kerr, K F A1 - Reiner, A P A1 - Rice, K M A1 - Roach, J A1 - Buckley, B M A1 - Soliman, E Z A1 - de Mutsert, R A1 - Sotoodehnia, N A1 - Uitterlinden, A G A1 - North, K E A1 - Lee, C R A1 - Gudnason, V A1 - Stürmer, T A1 - Rosendaal, F R A1 - Taylor, K D A1 - Wiggins, K L A1 - Wilson, J G A1 - Chen, Y-DI A1 - Kaplan, R C A1 - Wilhelmsen, K A1 - Cupples, L A A1 - Salomaa, V A1 - van Duijn, C A1 - Jukema, J W A1 - Liu, Y A1 - Mook-Kanamori, D O A1 - Lange, L A A1 - Vasan, R S A1 - Smith, A V A1 - Stricker, B H A1 - Laurie, C C A1 - Rotter, J I A1 - Whitsel, E A A1 - Psaty, B M A1 - Avery, C L AB -

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10(-8)), we found suggestive evidence (P<5 × 10(-6)) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.The Pharmacogenomics Journal advance online publication, 18 July 2017; doi:10.1038/tpj.2017.10.

ER - TY - JOUR T1 - Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. JF - Genome Biol Y1 - 2018 A1 - Prins, Bram P A1 - Mead, Timothy J A1 - Brody, Jennifer A A1 - Sveinbjornsson, Gardar A1 - Ntalla, Ioanna A1 - Bihlmeyer, Nathan A A1 - van den Berg, Marten A1 - Bork-Jensen, Jette A1 - Cappellani, Stefania A1 - Van Duijvenboden, Stefan A1 - Klena, Nikolai T A1 - Gabriel, George C A1 - Liu, Xiaoqin A1 - Gulec, Cagri A1 - Grarup, Niels A1 - Haessler, Jeffrey A1 - Hall, Leanne M A1 - Iorio, Annamaria A1 - Isaacs, Aaron A1 - Li-Gao, Ruifang A1 - Lin, Honghuang A1 - Liu, Ching-Ti A1 - Lyytikäinen, Leo-Pekka A1 - Marten, Jonathan A1 - Mei, Hao A1 - Müller-Nurasyid, Martina A1 - Orini, Michele A1 - Padmanabhan, Sandosh A1 - Radmanesh, Farid A1 - Ramirez, Julia A1 - Robino, Antonietta A1 - Schwartz, Molly A1 - van Setten, Jessica A1 - Smith, Albert V A1 - Verweij, Niek A1 - Warren, Helen R A1 - Weiss, Stefan A1 - Alonso, Alvaro A1 - Arnar, David O A1 - Bots, Michiel L A1 - de Boer, Rudolf A A1 - Dominiczak, Anna F A1 - Eijgelsheim, Mark A1 - Ellinor, Patrick T A1 - Guo, Xiuqing A1 - Felix, Stephan B A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Huang, Paul L A1 - Jukema, J W A1 - Kähönen, Mika A1 - Kors, Jan A A1 - Lambiase, Pier D A1 - Launer, Lenore J A1 - Li, Man A1 - Linneberg, Allan A1 - Nelson, Christopher P A1 - Pedersen, Oluf A1 - Perez, Marco A1 - Peters, Annette A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Rice, Kenneth M A1 - Rotter, Jerome I A1 - Sinner, Moritz F A1 - Soliman, Elsayed Z A1 - Spector, Tim D A1 - Strauch, Konstantin A1 - Thorsteinsdottir, Unnur A1 - Tinker, Andrew A1 - Trompet, Stella A1 - Uitterlinden, Andre A1 - Vaartjes, Ilonca A1 - van der Meer, Peter A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wilson, James G A1 - Xie, Zhijun A1 - Asselbergs, Folkert W A1 - Dörr, Marcus A1 - van Duijn, Cornelia M A1 - Gasparini, Paolo A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Kääb, Stefan A1 - Kanters, Jørgen K A1 - Kooperberg, Charles A1 - Lehtimäki, Terho A1 - Lin, Henry J A1 - Lubitz, Steven A A1 - Mook-Kanamori, Dennis O A1 - Conti, Francesco J A1 - Newton-Cheh, Christopher H A1 - Rosand, Jonathan A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Sinagra, Gianfranco A1 - Smith, Blair H A1 - Holm, Hilma A1 - Stricker, Bruno H A1 - Ulivi, Sheila A1 - Sotoodehnia, Nona A1 - Apte, Suneel S A1 - van der Harst, Pim A1 - Stefansson, Kari A1 - Munroe, Patricia B A1 - Arking, Dan E A1 - Lo, Cecilia W A1 - Jamshidi, Yalda AB -

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.

RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.

CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

VL - 19 IS - 1 ER - TY - JOUR T1 - Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry. JF - Pharmacogenomics J Y1 - 2019 A1 - de Las Fuentes, L A1 - Sung, Y J A1 - Sitlani, C M A1 - Avery, C L A1 - Bartz, T M A1 - Keyser, C de A1 - Evans, D S A1 - Li, X A1 - Musani, S K A1 - Ruiter, R A1 - Smith, A V A1 - Sun, F A1 - Trompet, S A1 - Xu, H A1 - Arnett, D K A1 - Bis, J C A1 - Broeckel, U A1 - Busch, E L A1 - Chen, Y-D I A1 - Correa, A A1 - Cummings, S R A1 - Floyd, J S A1 - Ford, I A1 - Guo, X A1 - Harris, T B A1 - Ikram, M A A1 - Lange, L A1 - Launer, L J A1 - Reiner, A P A1 - Schwander, K A1 - Smith, N L A1 - Sotoodehnia, N A1 - Stewart, J D A1 - Stott, D J A1 - Stürmer, T A1 - Taylor, K D A1 - Uitterlinden, A A1 - Vasan, R S A1 - Wiggins, K L A1 - Cupples, L A A1 - Gudnason, V A1 - Heckbert, S R A1 - Jukema, J W A1 - Liu, Y A1 - Psaty, B M A1 - Rao, D C A1 - Rotter, J I A1 - Stricker, B A1 - Wilson, J G A1 - Whitsel, E A AB -

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

ER -