Abstract
Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10−6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.
Highlights
Cognitive function can be classified into a number of domains such as reasoning, memory, verbal ability and information processing speed [1]
There is evidence for genome-wide association with the rs17518584 variant located within an intron of cell adhesion molecule 2 (CADM2) and information processing speed in a sample of 32,070 older adults of European ancestry [17], whereas no significant associations were found in two smaller studies in which there were 4038 participants from four cohorts [15] or 1086 young adults [16]
MATERIALS AND METHODS Study populations Nine population-based epidemiological cohort studies contributed to the discovery phase of the analysis: Age, Gene/Environment Susceptibility–Reykjavik Study (AGES-Reykjavik); Atherosclerosis Risk in Communities (ARIC) Study; Cardiovascular Health Study (CHS); Coronary Artery Risk Development in Young Adults (CARDIA); CROATIA-Korčula study (Korčula); Generation Scotland: Scottish Family Health Study (GS: SFHS); Genetic Epidemiology Network of Arteriopathy (GENOA); Lothian Birth Cohort 1921 (LBC1921); and Lothian Birth Cohort 1936 (LBC1936); Details for each cohort are described in the Supplementary Material
Summary
Cognitive function can be classified into a number of domains such as reasoning, memory, verbal ability and information processing speed [1]. Since heritability evaluated in twin studies has been estimated to be as high as 67% for inter-individual variation in performance on tests of processing speed [11,12,13,14], three genome-wide association studies (GWAS). There is evidence for genome-wide association with the rs17518584 variant located within an intron of CADM2 and information processing speed in a sample of 32,070 older adults of European ancestry [17], whereas no significant associations were found in two smaller studies in which there were 4038 participants from four cohorts [15] or 1086 young adults [16]. Twenty three genes were significantly associated with reaction time in the same study in gene-based analyses [18]
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