Genetic variants specific to aging-related verbal memory: Insights from GWASs in a population-based cohort

• Published in: PloS one Vol. 12; no. 8; p. e0182448
• Main Authors: Arpawong, Thalida E, Pendleton, Neil, Mekli, Krisztina, McArdle, John J, Gatz, Margaret, Armoskus, Chris, Knowles, James A, Prescott, Carol A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.08.2017; Public Library of Science (PLoS)
• Subjects: Adults; Age; Aged; Aged, 80 and over; Aging; Aging (Biology); Aging - genetics; Alleles; Alzheimer's disease; Alzheimers disease; Apolipoprotein E4; Apolipoprotein E4 - genetics; Apolipoproteins; Biology and Life Sciences; Brain research; Cognitive ability; Cohort Studies; Communication; Correlation analysis; Dementia; Female; Gene expression; Gene Regulatory Networks; Genetic aspects; Genetic diversity; Genetic markers; Genetic Variation; Genetics; Genome-Wide Association Study; Genomes; Genotype; Gerontology; Health; Health care; Humans; Infrared radiation; Male; Medicine and Health Sciences; Membrane Transport Proteins - genetics; Memory; Mental Recall; Meta-analysis; Middle Aged; Neurobiology; Neurosciences; Older people; Phenotypes; Physical Sciences; Polymorphism, Single Nucleotide - genetics; Population studies; Population-based studies; Preventive medicine; Recall; Regression analysis; Regression models; Research and Analysis Methods; Retirement; Risk Factors; Single-nucleotide polymorphism; Studies; Los Angeles California; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0182448

Verbal memory is typically studied using immediate recall (IR) and delayed recall (DR) scores, although DR is dependent on IR capability. Separating these components may be useful for deciphering the genetic variation in age-related memory abilities. This study was conducted to (a) construct individual trajectories in IR and independent aspects of delayed recall, or residualized-DR (rDR), across older adulthood; and (b) identify genetic markers that contribute to four estimated phenotypes: IR and rDR levels and changes after age 60. A cognitively intact sample (N = 20,650 with 125,164 observations) was drawn from the U.S. Health and Retirement Study, a nationally representative study of adults aged 50 and older. Mixed effects regression models were constructed using repeated measures from data collected every two years (1996-2012) to estimate level at age 60 and change in memory post-60 in IR and rDR. Genome-wide association scans (GWAS) were conducted in the genotypic subsample (N = 7,486) using ~1.2 million single nucleotide polymorphisms (SNPs). One SNP (rs2075650) in TOMM40 associated with rDR level at the genome-wide level (p = 5.0x10-08), an effect that replicated in an independent sample from the English Longitudinal Study on Ageing (N = 6,898 with 41,328 observations). Meta-analysis of rDR level confirmed the association (p = 5.0x10-11) and identified two others in TOMM40 (rs71352238 p = 1.0x10-10; rs157582 p = 7.0x10-09), and one in APOE (rs769449 p = 3.1 x10-12). Meta-analysis of IR change identified associations with three of the same SNPs in TOMM40 (rs157582 p = 8.3x10-10; rs71352238 p = 1.9x10-09) and APOE (rs769449 p = 2.2x10-08). Conditional analyses indicate GWAS signals on rDR level were driven by APOE, whereas signals on IR change were driven by TOMM40. Additionally, we found that TOMM40 had effects independent of APOE e4 on both phenotypes. Findings from this first U.S. population-based GWAS study conducted on both age-related immediate and delayed verbal memory merit continued examination in other samples and additional measures of verbal memory.