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Ultra-rare mutations in SRCAP segregate in Caribbean Hispanic families with Alzheimer disease.

ABSTRACT: OBJECTIVE:To identify rare coding variants segregating with late-onset Alzheimer disease (LOAD) in Caribbean Hispanic families. METHODS:Whole-exome sequencing (WES) was completed in 110 individuals from 31 Caribbean Hispanic families without APOE ?4 homozygous carriers. Rare coding mutations segregating in families were subsequently genotyped in additional families and in an independent cohort of Caribbean Hispanic patients and controls. SRCAP messenger RNA (mRNA) expression was assessed in whole blood from mutation carriers with LOAD, noncarriers with LOAD, and healthy elderly controls, and also from autopsied brains in 2 clinical neuropathologic cohort studies of aging and dementia. RESULTS:Ten ultra-rare missense mutations in the Snf2-related CREBBP, activator protein (SRCAP), were found in 12 unrelated families. Compared with the frequency in Caribbean Hispanic controls and the Latino population in the Exome Aggregation Consortium, the frequency of SRCAP mutations among Caribbean Hispanic patients with LOAD was significantly enriched (p = 1.19e-16). mRNA expression of SRCAP in whole blood was significantly lower in mutation carriers with LOAD, while the expression in whole blood and in the brain was significantly higher in nonmutation carriers with LOAD. Brain expression also correlated with clinical and neuropathologic endophenotypes. CONCLUSIONS:WES in Caribbean Hispanic families with LOAD revealed ultra-rare missense mutations in SRCAP, a gene expressed in the brain and mutated in Floating-Harbor syndrome. SRCAP is a potent coactivator of the CREB-binding protein and a regulator of DNA damage response involving ATP-dependent chromatin remodeling. We hypothesize that increased expression in LOAD suggests a compensatory mechanism altered in mutation carriers.

SUBMITTER: Vardarajan BN

PROVIDER: S-EPMC5570674 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Ultra-rare mutations in <i>SRCAP</i> segregate in Caribbean Hispanic families with Alzheimer disease.

Vardarajan Badri N BN Tosto Giuseppe G Lefort Roger R Yu Lei L Bennett David A DA De Jager Philip L PL Barral Sandra S Reyes-Dumeyer Dolly D Nagy Peter L PL Lee Joseph H JH Cheng Rong R Medrano Martin M Lantigua Rafael R Rogaeva Ekaterina E St George-Hyslop Peter P Mayeux Richard R

Neurology. Genetics 20170824 5

<h4>Objective</h4>To identify rare coding variants segregating with late-onset Alzheimer disease (LOAD) in Caribbean Hispanic families.<h4>Methods</h4>Whole-exome sequencing (WES) was completed in 110 individuals from 31 Caribbean Hispanic families without <i>APOE ε4</i> homozygous carriers. Rare coding mutations segregating in families were subsequently genotyped in additional families and in an independent cohort of Caribbean Hispanic patients and controls. <i>SRCAP</i> messenger RNA (mRNA) ex ...[more]

PMID: 28852706

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Project description:IMPORTANCE The search for novel Alzheimer disease (AD) genes or pathologic mutations within known AD loci is ongoing. The development of array technologies has helped to identify rare recessive mutations among long runs of homozygosity (ROHs), in which both parental alleles are identical. Caribbean Hispanics are known to have an elevated risk for AD and tend to have large families with evidence of inbreeding. OBJECTIVE To test the hypothesis that the late-onset AD in a Caribbean Hispanic population might be explained in part by the homozygosity of unknown loci that could harbor recessive AD risk haplotypes or pathologic mutations. DESIGN We used genome-wide array data to identify ROHs (>1 megabase) and conducted global burden and locus-specific ROH analyses. SETTING A whole-genome case-control ROH study. PARTICIPANTS A Caribbean Hispanic data set of 547 unrelated cases (48.8% with familial AD) and 542 controls collected from a population known to have a 3-fold higher risk of AD vs non-Hispanics in the same community. Based on a Structure program analysis, our data set consisted of African Hispanic (207 cases and 192 controls) and European Hispanic (329 cases and 326 controls) participants. EXPOSURE Alzheimer disease risk genes. MAIN OUTCOMES AND MEASURES We calculated the total and mean lengths of the ROHs per sample. Global burden measurements among autosomal chromosomes were investigated in cases vs controls. Pools of overlapping ROH segments (consensus regions) were identified, and the case to control ratio was calculated for each consensus region. We formulated the tested hypothesis before data collection. RESULTS In total, we identified 17 137 autosomal regions with ROHs. The mean length of the ROH per person was significantly greater in cases vs controls (P = .0039), and this association was stronger with familial AD (P = .0005). Among the European Hispanics, a consensus region at the EXOC4 locus was significantly associated with AD even after correction for multiple testing (empirical P value 1 [EMP1], .0001; EMP2, .002; 21 AD cases vs 2 controls). Among the African Hispanic subset, the most significant but nominal association was observed for CTNNA3, a well-known AD gene candidate (EMP1, .002; 10 AD cases vs 0 controls). CONCLUSIONS AND RELEVANCE Our results show that ROHs could significantly contribute to the etiology of AD. Future studies would require the analysis of larger, relatively inbred data sets that might reveal novel recessive AD genes. The next step is to conduct sequencing of top significant loci in a subset of samples with overlapping ROHs.

Dataset Information

Ultra-rare mutations in SRCAP segregate in Caribbean Hispanic families with Alzheimer disease.

Publications

Ultra-rare mutations in <i>SRCAP</i> segregate in Caribbean Hispanic families with Alzheimer disease.

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