title: Heritability and genetic association analysis of neuroimaging measures in the Diabetes Heart Study.
abstract: Patients with type 2 diabetes are at increased risk of age-related cognitive decline and dementia. Neuroimaging measures such as white matter lesion volume, brain volume, and fractional anisotropy may reflect the pathogenesis of these cognitive declines, and genetic factors may contribute to variability in these measures. This study examined multiple neuroimaging measures in 465 participants from 238 families with extensive genotype data in the type 2 diabetes enriched Diabetes Heart Study-Mind cohort. Heritability of these phenotypes and their association with candidate single-nucleotide polymorphisms (SNPs), and SNP data from genome- and exome-wide arrays were explored. All neuroimaging measures analyzed were significantly heritable (ĥ(2) = 0.55-0.99 in unadjusted models). Seventeen candidate SNPs (from 16 genes/regions) associated with neuroimaging phenotypes in prior studies showed no significant evidence of association. A missense variant (rs150706952, A432V) in PLEKHG4B from the exome-wide array was significantly associated with white matter mean diffusivity (p = 3.66 × 10(-7)) and gray matter mean diffusivity (p = 2.14 × 10(-7)). This analysis suggests genetic factors contribute to variation in neuroimaging measures in a population enriched for metabolic disease and other associated comorbidities.
authors.affiliation: Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston-Salem, NC, USA; Center for Genomics and Personalized Medicine Research, 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: Center for Genomics and Personalized Medicine Research, 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 Gerontology and Geriatrics, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Christina E
authors.initials: CE
authors.lastname: Hugenschmidt
authors.affiliation: Department of Internal Medicine-Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
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 Gerontology and Geriatrics, 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: Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Maldjian
authors.affiliation: Center for Genomics and Personalized Medicine Research, 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: D000368:Aged; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D015331:Cohort Studies; D003704:Dementia / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D066128:Gray Matter / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D009929:Organ Size / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012306:Risk; D013049:Spectrin / Q000235:genetics*; D066127:White Matter / Q000473:pathology*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C503982:PLEKHG4 protein, human; D013049:Spectrin
keywords: Genetics; Heritability; Magnetic resonance imaging; Type 2 diabetes