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.

The Worldwide Alzheimer's Disease Neuroimaging Initiative: An update

“…These efforts have led to the confirmation of several AD risk genes and the identification of novel risk loci, either alone [29] or as part of larger data sets provided by such consortia as Enhancing Neuro Imaging Genetics Through Meta Analysis or Cohorts for Heart and Aging Research in Genomic Epidemiology [30,31]. Further refinements to GWAS have included pathway and network analyses [32][33][34], the use of proteomics [35], and whole exome data [36], and copy number variant analysis. The latter refinement, in particular, has identified novel candidate AD susceptibility loci [37][38][39].…”

Alzheimer's Disease

“…In a study on AD cases and relevant controls, four genes were found to be associated with HV, including APOE, F5/SELP, LHFP, and GCFC2 (Melville et al, 2012). In a related study, two novel genes (CARD10 and PARP1) were found to affect hippocampal degeneration and HV in APOE e3/e3 individuals (Nho et al, 2013).…”

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

“…The gene had already been linked to the late onset form of AD (Rogaeva et al 2007), which has recently received replication in several independent studies (Jin et al 2013;Lambert et al 2013;Miyashita et al 2013;Wen et al 2013). Using exome sequencing and genotype imputation in MCI patients, Nho et al sought coding variants associated with rate of hippocampal volume loss in 16 patients, 8 of whom showed rapid rates of atrophy while 8 showed slow or steady rates of atrophy (Nho et al 2013). Three variants were found that were present in at least 6 of the rapid atrophy samples, but absent from the slow atrophy group in the genes HYAL4, PARP1, and CARD10, the latter two of which were predicted to be damaging by Polyphen-2.…”

“…Three variants were found that were present in at least 6 of the rapid atrophy samples, but absent from the slow atrophy group in the genes HYAL4, PARP1, and CARD10, the latter two of which were predicted to be damaging by Polyphen-2. Genetic variation within PARP1 and CARD10 was found to be associated with the rate of neurodegeneration in the hippocampus in APOE ε3/ε3 subjects (Nho et al 2013). CARD10 is involved in regulation of apoptosis and inflammation (Wang et al 2001;Nho et al 2013), while PARP1 has roles in a number of cellular processes, such as DNA repair, cell proliferation and cell death (Menissier de Murcia et al 2003;Nho et al 2013).…”

“…Genetic variation within PARP1 and CARD10 was found to be associated with the rate of neurodegeneration in the hippocampus in APOE ε3/ε3 subjects (Nho et al 2013). CARD10 is involved in regulation of apoptosis and inflammation (Wang et al 2001;Nho et al 2013), while PARP1 has roles in a number of cellular processes, such as DNA repair, cell proliferation and cell death (Menissier de Murcia et al 2003;Nho et al 2013). Its protein product had previously been reported to show enhanced activity in AD affected brains (Love et al 1999).…”