@article {6061, title = {Association of heat shock proteins with all-cause mortality.}, journal = {Age (Dordr)}, volume = {35}, year = {2013}, month = {2013 Aug}, pages = {1367-76}, abstract = {

Experimental mild heat shock is widely known as an intervention that results in extended longevity in various models along the evolutionary lineage. Heat shock proteins (HSPs) are highly upregulated immediately after a heat shock. The elevation in HSP levels was shown to inhibit stress-mediated cell death, and recent experiments indicate a highly versatile role for these proteins as inhibitors of programmed cell death. In this study, we examined common genetic variations in 31 genes encoding all members of the HSP70, small HSP, and heat shock factor (HSF) families for their association with all-cause mortality. Our discovery cohort was the Rotterdam study (RS1) containing 5,974 participants aged 55 years and older (3,174 deaths). We assessed 4,430 single nucleotide polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. After adjusting for multiple testing by permutation analysis, three SNPs showed evidence for association with all-cause mortality in RS1. These findings were followed in eight independent population-based cohorts, leading to a total of 25,007 participants (8,444 deaths). In the replication phase, only HSF2 (rs1416733) remained significantly associated with all-cause mortality. Rs1416733 is a known cis-eQTL for HSF2. Our findings suggest a role of HSF2 in all-cause mortality.

}, keywords = {Aged, 80 and over, Aging, Cause of Death, Forecasting, Genotype, Heat-Shock Proteins, Humans, Longevity, Promoter Regions, Genetic, Retrospective Studies, Transcription, Genetic, United States}, issn = {1574-4647}, doi = {10.1007/s11357-012-9417-7}, author = {Broer, L and Demerath, E W and Garcia, M E and Homuth, G and Kaplan, R C and Lunetta, K L and Tanaka, T and Tranah, G J and Walter, S and Arnold, A M and Atzmon, G and Harris, T B and Hoffmann, W and Karasik, D and Kiel, D P and Kocher, T and Launer, L J and Lohman, K K and Rotter, J I and Tiemeier, H and Uitterlinden, A G and Wallaschofski, H and Bandinelli, S and D{\"o}rr, M and Ferrucci, L and Franceschini, N and Gudnason, V and Hofman, A and Liu, Y and Murabito, J M and Newman, A B and Oostra, B A and Psaty, B M and Smith, A V and van Duijn, C M} } @article {6156, title = {Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer{\textquoteright}s disease.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Dec}, pages = {1452-8}, abstract = {

Eleven susceptibility loci for late-onset Alzheimer{\textquoteright}s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer{\textquoteright}s disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer{\textquoteright}s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 {\texttimes} 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer{\textquoteright}s disease.

}, keywords = {Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease, Case-Control Studies, Cohort Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.2802}, author = {Lambert, J C and Ibrahim-Verbaas, C A and Harold, D and Naj, A C and Sims, R and Bellenguez, C and DeStafano, A L and Bis, J C and Beecham, G W and Grenier-Boley, B and Russo, G and Thorton-Wells, T A and Jones, N and Smith, A V and Chouraki, V and Thomas, C and Ikram, M A and Zelenika, D and Vardarajan, B N and Kamatani, Y and Lin, C F and Gerrish, A and Schmidt, H and Kunkle, B and Dunstan, M L and Ruiz, A and Bihoreau, M T and Choi, S H and Reitz, C and Pasquier, F and Cruchaga, C and Craig, D and Amin, N and Berr, C and Lopez, O L and De Jager, P L and Deramecourt, V and Johnston, J A and Evans, D and Lovestone, S and Letenneur, L and Mor{\'o}n, F J and Rubinsztein, D C and Eiriksdottir, G and Sleegers, K and Goate, A M and Fi{\'e}vet, N and Huentelman, M W and Gill, M and Brown, K and Kamboh, M I and Keller, L and Barberger-Gateau, P and McGuiness, B and Larson, E B and Green, R and Myers, A J and Dufouil, C and Todd, S and Wallon, D and Love, S and Rogaeva, E and Gallacher, J and St George-Hyslop, P and Clarimon, J and Lleo, A and Bayer, A and Tsuang, D W and Yu, L and Tsolaki, M and Boss{\`u}, P and Spalletta, G and Proitsi, P and Collinge, J and Sorbi, S and Sanchez-Garcia, F and Fox, N C and Hardy, J and Deniz Naranjo, M C and Bosco, P and Clarke, R and Brayne, C and Galimberti, D and Mancuso, M and Matthews, F and Moebus, S and Mecocci, P and Del Zompo, M and Maier, W and Hampel, H and Pilotto, A and Bullido, M and Panza, F and Caffarra, P and Nacmias, B and Gilbert, J R and Mayhaus, M and Lannefelt, L and Hakonarson, H and Pichler, S and Carrasquillo, M M and Ingelsson, M and Beekly, D and Alvarez, V and Zou, F and Valladares, O and Younkin, S G and Coto, E and Hamilton-Nelson, K L and Gu, W and Razquin, C and Pastor, P and Mateo, I and Owen, M J and Faber, K M and Jonsson, P V and Combarros, O and O{\textquoteright}Donovan, M C and Cantwell, L B and Soininen, H and Blacker, D and Mead, S and Mosley, T H and Bennett, D A and Harris, T B and Fratiglioni, L and Holmes, C and de Bruijn, R F and Passmore, P and Montine, T J and Bettens, K and Rotter, J I and Brice, A and Morgan, K and Foroud, T M and Kukull, W A and Hannequin, D and Powell, J F and Nalls, M A and Ritchie, K and Lunetta, K L and Kauwe, J S and Boerwinkle, E and Riemenschneider, M and Boada, M and Hiltuenen, M and Martin, E R and Schmidt, R and Rujescu, D and Wang, L S and Dartigues, J F and Mayeux, R and Tzourio, C and Hofman, A and N{\"o}then, M M and Graff, C and Psaty, B M and Jones, L and Haines, J L and Holmans, P A and Lathrop, M and Pericak-Vance, M A and Launer, L J and Farrer, L A and van Duijn, C M and Van Broeckhoven, C and Moskvina, V and Seshadri, S and Williams, J and Schellenberg, G D and Amouyel, P} } @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 {6566, title = {Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.}, journal = {Mol Psychiatry}, volume = {20}, year = {2015}, month = {2015 Oct}, pages = {1232-9}, abstract = {

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 {\texttimes} 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 {\texttimes} 10(-4)). The strongest combined association was at rs1823125 (P=1.5 {\texttimes} 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

}, keywords = {Adult, African Americans, Aged, Dyssomnias, European Continental Ancestry Group, Female, Genetic Association Studies, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Self Report, Sleep}, issn = {1476-5578}, doi = {10.1038/mp.2014.133}, author = {Gottlieb, D J and Hek, K and Chen, T-H and Watson, N F and Eiriksdottir, G and Byrne, E M and Cornelis, M and Warby, S C and Bandinelli, S and Cherkas, L and Evans, D S and Grabe, H J and Lahti, J and Li, M and Lehtim{\"a}ki, T and Lumley, T and Marciante, K D and P{\'e}russe, L and Psaty, B M and Robbins, J and Tranah, G J and Vink, J M and Wilk, J B and Stafford, J M and Bellis, C and Biffar, R and Bouchard, C and Cade, B and Curhan, G C and Eriksson, J G and Ewert, R and Ferrucci, L and F{\"u}l{\"o}p, T and Gehrman, P R and Goodloe, R and Harris, T B and Heath, A C and Hernandez, D and Hofman, A and Hottenga, J-J and Hunter, D J and Jensen, M K and Johnson, A D and K{\"a}h{\"o}nen, M and Kao, L and Kraft, P and Larkin, E K and Lauderdale, D S and Luik, A I and Medici, M and Montgomery, G W and Palotie, A and Patel, S R and Pistis, G and Porcu, E and Quaye, L and Raitakari, O and Redline, S and Rimm, E B and Rotter, J I and Smith, A V and Spector, T D and Teumer, A and Uitterlinden, A G and Vohl, M-C and Widen, E and Willemsen, G and Young, T and Zhang, X and Liu, Y and Blangero, J and Boomsma, D I and Gudnason, V and Hu, F and Mangino, M and Martin, N G and O{\textquoteright}Connor, G T and Stone, K L and Tanaka, T and Viikari, J and Gharib, S A and Punjabi, N M and R{\"a}ikk{\"o}nen, K and V{\"o}lzke, H and Mignot, E and Tiemeier, H} } @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 {6680, title = {A novel Alzheimer disease locus located near the gene encoding tau protein.}, journal = {Mol Psychiatry}, volume = {21}, year = {2016}, month = {2016 Jan}, pages = {108-17}, abstract = {

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer{\textquoteright}s Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 {\texttimes} 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5{\textperiodcentered}8 {\texttimes} 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1{\textperiodcentered}6 {\texttimes} 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 {\texttimes} 10(-8)), frontal cortex (P ⩽ 1.3 {\texttimes} 10(-9)) and temporal cortex (P⩽1.2 {\texttimes} 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 {\texttimes} 10(-6)) and temporal cortex (P=2.6 {\texttimes} 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

}, keywords = {Alzheimer Disease, Apolipoprotein E4, Chromosomes, Human, Pair 17, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, tau Proteins}, issn = {1476-5578}, doi = {10.1038/mp.2015.23}, author = {Jun, G and Ibrahim-Verbaas, C A and Vronskaya, M and Lambert, J-C and Chung, J and Naj, A C and Kunkle, B W and Wang, L-S and Bis, J C and Bellenguez, C and Harold, D and Lunetta, K L and DeStefano, A L and Grenier-Boley, B and Sims, R and Beecham, G W and Smith, A V and Chouraki, V and Hamilton-Nelson, K L and Ikram, M A and Fi{\'e}vet, N and Denning, N and Martin, E R and Schmidt, H and Kamatani, Y and Dunstan, M L and Valladares, O and Laza, A R and Zelenika, D and Ramirez, A and Foroud, T M and Choi, S-H and Boland, A and Becker, T and Kukull, W A and van der Lee, S J and Pasquier, F and Cruchaga, C and Beekly, D and Fitzpatrick, A L and Hanon, O and Gill, M and Barber, R and Gudnason, V and Campion, D and Love, S and Bennett, D A and Amin, N and Berr, C and Tsolaki, Magda and Buxbaum, J D and Lopez, O L and Deramecourt, V and Fox, N C and Cantwell, L B and T{\'a}rraga, L and Dufouil, C and Hardy, J and Crane, P K and Eiriksdottir, G and Hannequin, D and Clarke, R and Evans, D and Mosley, T H and Letenneur, L and Brayne, C and Maier, W and De Jager, P and Emilsson, V and Dartigues, J-F and Hampel, H and Kamboh, M I and de Bruijn, R F A G and Tzourio, C and Pastor, P and Larson, E B and Rotter, J I and O{\textquoteright}Donovan, M C and Montine, T J and Nalls, M A and Mead, S and Reiman, E M and Jonsson, P V and Holmes, C and St George-Hyslop, P H and Boada, M and Passmore, P and Wendland, J R and Schmidt, R and Morgan, K and Winslow, A R and Powell, J F and Carasquillo, M and Younkin, S G and Jakobsd{\'o}ttir, J and Kauwe, J S K and Wilhelmsen, K C and Rujescu, D and N{\"o}then, M M and Hofman, A and Jones, L and Haines, J L and Psaty, B M and Van Broeckhoven, C and Holmans, P and Launer, L J and Mayeux, R and Lathrop, M and Goate, A M and Escott-Price, V and Seshadri, S and Pericak-Vance, M A and Amouyel, P and Williams, J and van Duijn, C M and Schellenberg, G D and Farrer, L A} } @article {7491, title = {Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.}, journal = {Pharmacogenomics J}, year = {2017}, month = {2017 Jul 18}, abstract = {

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 {\texttimes} 10(-8)), we found suggestive evidence (P<5 {\texttimes} 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.

}, issn = {1473-1150}, doi = {10.1038/tpj.2017.10}, author = {Seyerle, A A and Sitlani, C M and Noordam, R and Gogarten, S M and Li, J and Li, X and Evans, D S and Sun, F and Laaksonen, M A and Isaacs, A and Kristiansson, K and Highland, H M and Stewart, J D and Harris, T B and Trompet, S and Bis, J C and Peloso, G M and Brody, J A and Broer, L and Busch, E L and Duan, Q and Stilp, A M and O{\textquoteright}Donnell, C J and Macfarlane, P W and Floyd, J S and Kors, J A and Lin, H J and Li-Gao, R and Sofer, T and M{\'e}ndez-Gir{\'a}ldez, R and Cummings, S R and Heckbert, S R and Hofman, A and Ford, I and Li, Y and Launer, L J and Porthan, K and Newton-Cheh, C and Napier, M D and Kerr, K F and Reiner, A P and Rice, K M and Roach, J and Buckley, B M and Soliman, E Z and de Mutsert, R and Sotoodehnia, N and Uitterlinden, A G and North, K E and Lee, C R and Gudnason, V and St{\"u}rmer, T and Rosendaal, F R and Taylor, K D and Wiggins, K L and Wilson, J G and Chen, Y-DI and Kaplan, R C and Wilhelmsen, K and Cupples, L A and Salomaa, V and van Duijn, C and Jukema, J W and Liu, Y and Mook-Kanamori, D O and Lange, L A and Vasan, R S and Smith, A V and Stricker, B H and Laurie, C C and Rotter, J I and Whitsel, E A and Psaty, B M and Avery, C L} } @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} }