title: Investigating the genetics of hippocampal volume in older adults without dementia.
abstract: Hippocampal atrophy is observed with ageing and age-related neurodegenerative disease. Identification of the genetic correlates of hippocampal volume (HV) and atrophy may assist in elucidating the mechanisms of ageing and age-related neurodegeneration. Using two community cohorts of older Caucasians we estimated the heritability of HV and examined associations of HV with previously identified single nucleotide polymorphisms (SNPs). In addition we undertook genome-association studies (GWAS) examining HV and HV atrophy. Participants were community-dwelling non-demented older adults from the longitudinal Sydney Memory and Ageing Study (Sydney MAS) (N = 498) and the Older Australian Twins Study (OATS) (N = 351) aged 65 and over. HV was measured using T1-weighted magnetic resonance images. Heritability of HV was estimated in OATS. Genome-wide genotyping was imputed using the 1K Genomes reference set. Associations with HV-candidate and Alzheimer's disease (AD)-related SNPs were investigated. A GWAS examining HV (in both cohorts) and an exploratory GWAS of HV atrophy over two years (in Sydney MAS only) were also undertaken. HV heritability was estimated at 62-65%. The previously identified GWAS HV SNP (rs6581612) and the candidate BDNF SNP (rs6265) were nominally significant (p = 0.047 and p = 0.041 respectively). No AD-related SNPs, including the APOE ε4 polymorphism, were significant. No significant results were observed for either of the GWAS undertaken. Despite our estimate of a high heritability of HV, our results are consistent with a highly polygenic model suggesting that SNPs identified from prior studies, including GWAS meta-analyses, can be difficult to replicate in smaller samples of older adults.
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales (UNSW), Sydney, Australia.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Mather
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales (UNSW), Sydney, Australia; School of Mathematics and Statistics, University of Sydney, Sydney, Australia; School of Mathematics and Statistics, UNSW, Sydney, Australia.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Armstrong
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales (UNSW), Sydney, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Wen
authors.affiliation: Neuroscience Research Australia, Sydney, Australia; School of Medical Sciences, UNSW, Sydney, Australia.
authors.forename: John B
authors.initials: JB
authors.lastname: Kwok
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales (UNSW), Sydney, Australia.
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Assareh
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales (UNSW), Sydney, Australia.
authors.forename: Anbupalam
authors.initials: A
authors.lastname: Thalamuthu
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales (UNSW), Sydney, Australia.
authors.forename: Simone
authors.initials: S
authors.lastname: Reppermund
authors.affiliation: The Commonwealth Scientific and Industrial Research Organisation (CSIRO) Animal Food and Health Sciences Division, Sydney, Australia.
authors.forename: Konsta
authors.initials: K
authors.lastname: Duesing
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Wright
authors.affiliation: National Ageing Research Institute, Royal Melbourne Hospital, Melbourne, Australia; Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Ames
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales (UNSW), Sydney, Australia; Department of Developmental Disability Neuropsychiatry, UNSW, Sydney, Australia.
authors.forename: Julian N
authors.initials: JN
authors.lastname: Trollor
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales (UNSW), Sydney, Australia; Primary Dementia Collaborative Research Centre, UNSW, Sydney, Australia.
authors.forename: Henry
authors.initials: H
authors.lastname: Brodaty
authors.affiliation: Neuroscience Research Australia, Sydney, Australia; School of Medical Sciences, UNSW, Sydney, Australia.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Schofield
authors.affiliation: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales (UNSW), Sydney, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia.
authors.forename: Perminder S
authors.initials: PS
authors.lastname: Sachdev
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D003704:Dementia / Q000473:pathology; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008297:Male; D009929:Organ Size / Q000235:genetics; D020641:Polymorphism, Single Nucleotide