title: Heritability and genetic association analysis of cognition in the Diabetes Heart Study.
abstract: Cognitive performance is an important component of healthy aging. Type 2 diabetes (T2D) is associated with negative outcomes for the brain and cognition, although causal mechanisms have not been definitely determined. Genetic risk factors warrant further consideration in this context. This study examined the heritability of cognitive function as assessed by (1) the Digit Symbol Substitution Task; (2) the Modified Mini-Mental State Examination; (3) the Stroop Task; (4) the Rey Auditory-Verbal Learning Task; and (5) the Controlled Oral Word Association Task for Phonemic and Semantic Fluency, in the family-based, T2D-enriched, Diabetes Heart Study sample (n = 550 participants from 257 families). The genetic basis of these cognitive measures was further evaluated by association analysis with candidate single-nucleotide polymorphisms (SNPs) and genome-wide SNP data. Measures of cognitive function were significantly heritable (hˆ(2) = 0.28-0.62) following adjustment for age, gender, and education. A total of 31 SNPs (from 26 genes/regions) selected to form an a priori set of candidate SNPs showed limited evidence of association with cognitive function when applying conservative metrics of significance. Genome-wide assessment of both noncoding and coding variants revealed suggestive evidence of association for several coding variants including rs139509083 in CNST (p = 4.9 × 10(-9)), rs199968569 in PLAA (p = 4.9 × 10(-9)) and rs138487371 in PCDH8 (p = 3.7 × 10(-8)). The identification of a heritable component to cognitive performance in T2D suggests a role for genetic contributors to cognitive performance even in the presence of metabolic disease and other associated comorbidities and is supported by the identification of genetic association signals in functionally plausible candidates.
authors.affiliation: Center for Human Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA; Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Cox
authors.affiliation: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Christina E
authors.initials: CE
authors.lastname: Hugenschmidt
authors.affiliation: Center for Human Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA; Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Raffield
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Jeff D
authors.initials: JD
authors.lastname: Williamson
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Fang-Chi
authors.initials: FC
authors.lastname: Hsu
authors.affiliation: Center for Human Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA; Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA. Electronic address: dbowden@wakehealth.edu.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003071:Cognition / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000523:psychology*; D004522:Educational Status; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
keywords: Cognitive function; Genetics; Heritability; Type 2 diabetes