@article {5978, title = {Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.}, journal = {Pharmacogenomics J}, volume = {14}, year = {2014}, month = {2014 Feb}, pages = {6-13}, abstract = {

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the {\textquoteright}missing heritability{\textquoteright} 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 {\texttimes} 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

}, keywords = {Computer Simulation, Cross-Sectional Studies, Drug-Related Side Effects and Adverse Reactions, Electrocardiography, European Continental Ancestry Group, Gene-Environment Interaction, Genome-Wide Association Study, Humans, Linear Models, Long QT Syndrome, Markov Chains, Pharmacogenetics, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable}, issn = {1473-1150}, doi = {10.1038/tpj.2013.4}, author = {Avery, C L and Sitlani, C M and Arking, D E and Arnett, D K and Bis, J C and Boerwinkle, E and Buckley, B M and Ida Chen, Y-D and de Craen, A J M and Eijgelsheim, M and Enquobahrie, D and Evans, D S and Ford, I and Garcia, M E and Gudnason, V and Harris, T B and Heckbert, S R and Hochner, H and Hofman, A and Hsueh, W-C and Isaacs, A and Jukema, J W and Knekt, P and Kors, J A and Krijthe, B P and Kristiansson, K and Laaksonen, M and Liu, Y and Li, X and Macfarlane, P W and Newton-Cheh, C and Nieminen, M S and Oostra, B A and Peloso, G M and Porthan, K and Rice, K and Rivadeneira, F F and Rotter, J I and Salomaa, V and Sattar, N and Siscovick, D S and Slagboom, P E and Smith, A V and Sotoodehnia, N and Stott, D J and Stricker, B H and St{\"u}rmer, T and Trompet, S and Uitterlinden, A G and van Duijn, C and Westendorp, R G J and Witteman, J C and Whitsel, E A and Psaty, B M} } @article {6816, title = {Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).}, journal = {Mol Psychiatry}, volume = {20}, year = {2015}, month = {2015 Feb}, pages = {183-92}, abstract = {

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 {\texttimes} 10(-9), MIR2113; rs17522122, P=2.55 {\texttimes} 10(-8), AKAP6; rs10119, P=5.67 {\texttimes} 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 {\texttimes} 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 {\texttimes} 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer{\textquoteright}s disease: TOMM40, APOE, ABCG1 and MEF2C.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Cognition, Cognition Disorders, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, HMGN1 Protein, Humans, Male, Middle Aged, Neuropsychological Tests, Phenotype, Polymorphism, Single Nucleotide, Scotland}, issn = {1476-5578}, doi = {10.1038/mp.2014.188}, author = {Davies, G and Armstrong, N and Bis, J C and Bressler, J and Chouraki, V and Giddaluru, S and Hofer, E and Ibrahim-Verbaas, C A and Kirin, M and Lahti, J and van der Lee, S J and Le Hellard, S and Liu, T and Marioni, R E and Oldmeadow, C and Postmus, I and Smith, A V and Smith, J A and Thalamuthu, A and Thomson, R and Vitart, V and Wang, J and Yu, L and Zgaga, L and Zhao, W and Boxall, R and Harris, S E and Hill, W D and Liewald, D C and Luciano, M and Adams, H and Ames, D and Amin, N and Amouyel, P and Assareh, A A and Au, R and Becker, J T and Beiser, A and Berr, C and Bertram, L and Boerwinkle, E and Buckley, B M and Campbell, H and Corley, J and De Jager, P L and Dufouil, C and Eriksson, J G and Espeseth, T and Faul, J D and Ford, I and Gottesman, R F and Griswold, M E and Gudnason, V and Harris, T B and Heiss, G and Hofman, A and Holliday, E G and Huffman, J and Kardia, S L R and Kochan, N and Knopman, D S and Kwok, J B and Lambert, J-C and Lee, T and Li, G and Li, S-C and Loitfelder, M and Lopez, O L and Lundervold, A J and Lundqvist, A and Mather, K A and Mirza, S S and Nyberg, L and Oostra, B A and Palotie, A and Papenberg, G and Pattie, A and Petrovic, K and Polasek, O and Psaty, B M and Redmond, P and Reppermund, S and Rotter, J I and Schmidt, H and Schuur, M and Schofield, P W and Scott, R J and Steen, V M and Stott, D J and van Swieten, J C and Taylor, K D and Trollor, J and Trompet, S and Uitterlinden, A G and Weinstein, G and Widen, E and Windham, B G and Jukema, J W and Wright, A F and Wright, M J and Yang, Q and Amieva, H and Attia, J R and Bennett, D A and Brodaty, H and de Craen, A J M and Hayward, C and Ikram, M A and Lindenberger, U and Nilsson, L-G and Porteous, D J and R{\"a}ikk{\"o}nen, K and Reinvang, I and Rudan, I and Sachdev, P S and Schmidt, R and Schofield, P R and Srikanth, V and Starr, J M and Turner, S T and Weir, D R and Wilson, J F and van Duijn, C and Launer, L and Fitzpatrick, A L and Seshadri, S and Mosley, T H and Deary, I J} } @article {6799, title = {GWAS for executive function and processing speed suggests involvement of the CADM2 gene.}, journal = {Mol Psychiatry}, volume = {21}, year = {2016}, month = {2016 Feb}, pages = {189-97}, abstract = {

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 {\texttimes} 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 {\texttimes} 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 {\texttimes} 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 {\texttimes} 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 {\texttimes} 10(-11)) and neuron cell-cell adhesion (P-value=1.48 {\texttimes} 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

}, issn = {1476-5578}, doi = {10.1038/mp.2015.37}, author = {Ibrahim-Verbaas, C A and Bressler, J and Debette, S and Schuur, M and Smith, A V and Bis, J C and Davies, G and Trompet, S and Smith, J A and Wolf, C and Chibnik, L B and Liu, Y and Vitart, V and Kirin, M and Petrovic, K and Polasek, O and Zgaga, L and Fawns-Ritchie, C and Hoffmann, P and Karjalainen, J and Lahti, J and Llewellyn, D J and Schmidt, C O and Mather, K A and Chouraki, V and Sun, Q and Resnick, S M and Rose, L M and Oldmeadow, C and Stewart, M and Smith, B H and Gudnason, V and Yang, Q and Mirza, S S and Jukema, J W and deJager, P L and Harris, T B and Liewald, D C and Amin, N and Coker, L H and Stegle, O and Lopez, O L and Schmidt, R and Teumer, A and Ford, I and Karbalai, N and Becker, J T and Jonsdottir, M K and Au, R and Fehrmann, R S N and Herms, S and Nalls, M and Zhao, W and Turner, S T and Yaffe, K and Lohman, K and van Swieten, J C and Kardia, S L R and Knopman, D S and Meeks, W M and Heiss, G and Holliday, E G and Schofield, P W and Tanaka, T and Stott, D J and Wang, J and Ridker, P and Gow, A J and Pattie, A and Starr, J M and Hocking, L J and Armstrong, N J and McLachlan, S and Shulman, J M and Pilling, L C and Eiriksdottir, G and Scott, R J and Kochan, N A and Palotie, A and Hsieh, Y-C and Eriksson, J G and Penman, A and Gottesman, R F and Oostra, B A and Yu, L and DeStefano, A L and Beiser, A and Garcia, M and Rotter, J I and N{\"o}then, M M and Hofman, A and Slagboom, P E and Westendorp, R G J and Buckley, B M and Wolf, P A and Uitterlinden, A G and Psaty, B M and Grabe, H J and Bandinelli, S and Chasman, D I and Grodstein, F and R{\"a}ikk{\"o}nen, K and Lambert, J-C and Porteous, D J and Price, J F and Sachdev, P S and Ferrucci, L and Attia, J R and Rudan, I and Hayward, C and Wright, A F and Wilson, J F and Cichon, S and Franke, L and Schmidt, H and Ding, J and de Craen, A J M and Fornage, M and Bennett, D A and Deary, I J and Ikram, M A and Launer, L J and Fitzpatrick, A L and Seshadri, S and van Duijn, C M and Mosley, T H} } @article {7253, title = {Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.}, journal = {Pharmacogenomics J}, year = {2016}, month = {2016 Dec 13}, abstract = {

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 {\texttimes} 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.

}, issn = {1473-1150}, doi = {10.1038/tpj.2016.90}, author = {Floyd, J S and Sitlani, C M and Avery, C L and Noordam, R and Li, X and Smith, A V and Gogarten, S M and Li, J and Broer, L and Evans, D S and Trompet, S and Brody, J A and Stewart, J D and Eicher, J D and Seyerle, A A and Roach, J and Lange, L A and Lin, H J and Kors, J A and Harris, T B and Li-Gao, R and Sattar, N and Cummings, S R and Wiggins, K L and Napier, M D and St{\"u}rmer, T and Bis, J C and Kerr, K F and Uitterlinden, A G and Taylor, K D and Stott, D J and de Mutsert, R and Launer, L J and Busch, E L and M{\'e}ndez-Gir{\'a}ldez, R and Sotoodehnia, N and Soliman, E Z and Li, Y and Duan, Q and Rosendaal, F R and Slagboom, P E and Wilhelmsen, K C and Reiner, A P and Chen, Y-DI and Heckbert, S R and Kaplan, R C and Rice, K M and Jukema, J W and Johnson, A D and Liu, Y and Mook-Kanamori, D O and Gudnason, V and Wilson, J G and Rotter, J I and Laurie, C C and Psaty, B M and Whitsel, E A and Cupples, L A and Stricker, B H} } @article {8260, title = {Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.}, journal = {Pharmacogenomics J}, year = {2019}, month = {2019 Dec 06}, abstract = {

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 {\texttimes} 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.

}, issn = {1473-1150}, doi = {10.1038/s41397-019-0132-y}, author = {de Las Fuentes, L and Sung, Y J and Sitlani, C M and Avery, C L and Bartz, T M and Keyser, C de and Evans, D S and Li, X and Musani, S K and Ruiter, R and Smith, A V and Sun, F and Trompet, S and Xu, H and Arnett, D K and Bis, J C and Broeckel, U and Busch, E L and Chen, Y-D I and Correa, A and Cummings, S R and Floyd, J S and Ford, I and Guo, X and Harris, T B and Ikram, M A and Lange, L and Launer, L J and Reiner, A P and Schwander, K and Smith, N L and Sotoodehnia, N and Stewart, J D and Stott, D J and St{\"u}rmer, T and Taylor, K D and Uitterlinden, A and Vasan, R S and Wiggins, K L and Cupples, L A and Gudnason, V and Heckbert, S R and Jukema, J W and Liu, Y and Psaty, B M and Rao, D C and Rotter, J I and Stricker, B and Wilson, J G and Whitsel, E A} }