title: Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment.
abstract: Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.
authors.affiliation: Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN 46202-3082, USA.
authors.forename: K
authors.initials: K
authors.lastname: Nho
authors.forename: J J
authors.initials: JJ
authors.lastname: Corneveaux
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: H
authors.initials: H
authors.lastname: Lin
authors.forename: S L
authors.initials: SL
authors.lastname: Risacher
authors.forename: L
authors.initials: L
authors.lastname: Shen
authors.forename: S
authors.initials: S
authors.lastname: Swaminathan
authors.forename: V K
authors.initials: VK
authors.lastname: Ramanan
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Foroud
authors.forename: M H
authors.initials: MH
authors.lastname: Inlow
authors.forename: A L
authors.initials: AL
authors.lastname: Siniard
authors.forename: R A
authors.initials: RA
authors.lastname: Reiman
authors.forename: P S
authors.initials: PS
authors.lastname: Aisen
authors.forename: R C
authors.initials: RC
authors.lastname: Petersen
authors.forename: R C
authors.initials: RC
authors.lastname: Green
authors.forename: C R
authors.initials: CR
authors.lastname: Jack
authors.forename: M W
authors.initials: MW
authors.lastname: Weiner
authors.forename: C T
authors.initials: CT
authors.lastname: Baldwin
authors.forename: K
authors.initials: K
authors.lastname: Lunetta
authors.forename: L A
authors.initials: LA
authors.lastname: Farrer
authors.forename: S J
authors.initials: SJ
authors.lastname: Furney
authors.forename: S
authors.initials: S
authors.lastname: Lovestone
authors.forename: A
authors.initials: A
authors.lastname: Simmons
authors.forename: P
authors.initials: P
authors.lastname: Mecocci
authors.forename: B
authors.initials: B
authors.lastname: Vellas
authors.forename: M
authors.initials: M
authors.lastname: Tsolaki
authors.forename: I
authors.initials: I
authors.lastname: Kloszewska
authors.forename: H
authors.initials: H
authors.lastname: Soininen
authors.forename: B C
authors.initials: BC
authors.lastname: McDonald
authors.forename: M R
authors.initials: MR
authors.lastname: Farlow
authors.forename: B
authors.initials: B
authors.lastname: Ghetti
authors.forename: M J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: A J
authors.initials: AJ
authors.lastname: Saykin
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000523:psychology; D053318:Apolipoprotein E3 / Q000235:genetics; D001284:Atrophy / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D060825:Cognitive Dysfunction / Q000150:complications / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D059472:Exome / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008297:Male; D059906:Neuroimaging; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D053318:Apolipoprotein E3; D053468:CARD Signaling Adaptor Proteins; C430880:CARD10 protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases