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Polygenic risk for coronary artery disease is associated with cognitive ability in older adults.

ABSTRACT: Coronary artery disease (CAD) is associated with cognitive decrements and risk of later dementia, but it is not known if shared genetic factors underlie this association. We tested whether polygenic risk for CAD was associated with cognitive ability in community-dwelling cohorts of middle-aged and older adults.Individuals from Generation Scotland: Scottish Family Health Study (GS:SFHS, N = 9865) and from the Lothian Birth Cohorts of 1921 (LBC1921, N?=?517) and 1936 (LBC1936, N?=?1005) provided cognitive data and genome-wide genotype data. Polygenic risk profile scores for CAD were calculated for all of the cohorts using the largest available genome-wide association studies (GWAS) data set, the CARDIoGRAM consortium (22?233 cases and 64?762 controls). Polygenic risk profile scores for CAD were then tested for their association with cognitive abilities in the presence and absence of manifest cardiovascular disease.A meta-analysis of all three cohorts showed a negative association between CAD polygenic risk and fluid cognitive ability (??=?-0.022, P?=?0.016), verbal intelligence (??=?-0.024, P?=?0.011) and memory (??=?-0.021, P?=?0.028).Increased polygenic risk for CAD is associated with lower cognitive ability in older adults. Common genetic variants may underlie some of the association between age-related cognitive decrements and the risk for CAD.

SUBMITTER: Hagenaars SP

PROVIDER: S-EPMC4864876 | biostudies-other | 2016 Jan

REPOSITORIES: biostudies-other

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Polygenic risk for coronary artery disease is associated with cognitive ability in older adults.

Hagenaars Saskia P SP Harris Sarah E SE Clarke Toni-Kim TK Hall Lynsey L Luciano Michelle M Fernandez-Pujals Ana Maria AM Davies Gail G Hayward Caroline C Starr John M JM Porteous David J DJ McIntosh Andrew M AM Deary Ian J IJ

International journal of epidemiology 20160128 2

<h4>Background</h4>Coronary artery disease (CAD) is associated with cognitive decrements and risk of later dementia, but it is not known if shared genetic factors underlie this association. We tested whether polygenic risk for CAD was associated with cognitive ability in community-dwelling cohorts of middle-aged and older adults.<h4>Methods</h4>Individuals from Generation Scotland: Scottish Family Health Study (GS:SFHS, N = 9865) and from the Lothian Birth Cohorts of 1921 (LBC1921, N = 517) and ...[more]

PMID: 26822939

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Project description:Sex-differences in human liver gene expression were characterized on a genome-wide scale using a large liver sample collection, allowing for detection of small expression differences with high statistical power. 1,249 sex-biased genes were identified, 70% showing higher expression in females. Chromosomal bias was apparent, with female-biased genes enriched on chrX and male-biased genes enriched on chrY and chr19, where 11 male-biased zinc-finger KRAB-repressor domain genes are distributed in six clusters. Top biological functions and diseases significantly enriched in sex-biased genes include transcription, chromatin organization and modification, sexual reproduction, lipid metabolism and cardiovascular disease. Notably, sex-biased genes are enriched at loci associated with polygenic dyslipidemia and coronary artery disease in genome-wide association studies. Moreover, of the 8 sex-biased genes at these loci, 4 have been directly linked to monogenic disorders of lipid metabolism and show an expression profile in females (elevated expression of ABCA1, APOA5 and LDLR; reduced expression of LIPC) that is consistent with the lower female risk of coronary artery disease. Female-biased expression was also observed for CYP7A1, which is activated by drugs used to treat hypercholesterolemia. Several sex-biased drug-metabolizing enzyme genes were identified, including members of the CYP, UGT, GPX and ALDH families. Half of 879 mouse orthologs, including many genes of lipid metabolism and homeostasis, show growth hormone-regulated sex-biased expression in mouse liver, suggesting growth hormone might play a similar regulatory role in human liver. Finally, the evolutionary rate of protein-coding regions for human-mouse orthologs, revealed by dN/dS ratio, is significantly higher for genes showing the same sex-bias in both species than for non-sex-biased genes. These findings establish that human hepatic sex differences are widespread and affect diverse cell metabolic processes, and may help explain sex differences in lipid profiles associated with sex differential risk of coronary artery disease. A first set of randomized liver RNA pools (WS9) was generated by randomly distributing 112 male and 112 female liver RNA samples into 8 pools comprised of 14 male liver samples (pools M1 to M8), and 8 pools of 14 female liver samples each (pools F1 to F8). A second set of 16 pools (WS10) was prepared from the same set of 224 liver samples in the same way (pools M9 to M16 and F9 to F16). The 16 liver RNA pools of each sex were used in a total of 16 male vs. female two-color hybridization microarrays by pairing pool M1 and pool F1, pool M2 with pool F2, etc. Fluorescent labeling of RNA and hybridization of the Alexa 555-labeled and Alexa 647-labeled amplified RNA samples to Agilent Whole Human Genome oligonucleotide microarrays (4 x 44K format; Agilent Technology, Palo Alto, CA; catalog # G4112F) were carried out, with dye swaps to eliminate dye bias.

Dataset Information

Polygenic risk for coronary artery disease is associated with cognitive ability in older adults.

Publications

Polygenic risk for coronary artery disease is associated with cognitive ability in older adults.

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