@article {6063, title = {Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.}, journal = {Heart Rhythm}, volume = {10}, year = {2013}, month = {2013 Mar}, pages = {401-8}, abstract = {

BACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans.

OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans.

METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P<=2.5{\texttimes}10(-8)).

RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98{\texttimes}10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans.

CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

}, keywords = {Adult, African Americans, Aged, Arrhythmias, Cardiac, Connexin 43, Electrocardiography, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Heart Rate, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Rest, United States}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2012.11.014}, author = {Deo, R and Nalls, M A and Avery, C L and Smith, J G and Evans, D S and Keller, M F and Butler, A M and Buxbaum, S G and Li, G and Miguel Quibrera, P and Smith, E N and Tanaka, T and Akylbekova, E L and Alonso, A and Arking, D E and Benjamin, E J and Berenson, G S and Bis, J C and Chen, L Y and Chen, W and Cummings, S R and Ellinor, P T and Evans, M K and Ferrucci, L and Fox, E R and Heckbert, S R and Heiss, G and Hsueh, W C and Kerr, K F and Limacher, M C and Liu, Y and Lubitz, S A and Magnani, J W and Mehra, R and Marcus, G M and Murray, S S and Newman, A B and Njajou, O and North, K E and Paltoo, D N and Psaty, B M and Redline, S S and Reiner, A P and Robinson, J G and Rotter, J I and Samdarshi, T E and Schnabel, R B and Schork, N J and Singleton, A B and Siscovick, D and Soliman, E Z and Sotoodehnia, N and Srinivasan, S R and Taylor, H A and Trevisan, M and Zhang, Z and Zonderman, A B and Newton-Cheh, C and Whitsel, E A} } @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} }