Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals

作者：Ghani Mahdi; Reitz Christiane; Cheng Rong; Vardarajan Badri Narayan; Jun Gyungah; Sato Christine; Naj Adam; Rajbhandary Ruchita; Wang Li San; Valladares Otto; Lin Chiao Feng; Larson Eric B; Graff Radford Neill R; Evans Denis; De Jager Philip L; Crane Paul K; Buxbaum Joseph D; Murrell Jill R; Raj Towfique; Ertekin Taner Nilufer; Logue Mark; Baldwin Clinton T; Green Robert C; Barnes Lisa L; Cantwell Laura B; Fallin M Daniele; Go Rodney C P

来源：JAMA Neurology, 2015, 72(11): 1313-1323.

DOI：10.1001/jamaneurol.2015.1700

IMPORTANCE Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays.
OBJECTIVE To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals.
DESIGN, SETTING, AND PARTICIPANTS Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using rawor imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals.
MAIN OUTCOMES AND MEASURES The ROHs larger than 1Mb, 2Mb, or 3Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses.
RESULTS The African American cohort had a lowdegree of inbreeding (F = 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2Mb (P =.004) or greater than 3Mb (P=.02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 =.04; ROHs > 2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 =.02; ROHs > 1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 =.03; ROHs > 3 Mb). A total of 43 of 49 nominally significant genescommonfor both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs > 1Mbin cases vs 12.11 in controls; 2.986Mbaverage size of ROHs > 2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs > 3Mbvs19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2=.006-.04; ROHs > 3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 =.01; ROHs > 1 Mb), encoding a protein from the Claudin family, members of whichwere previously suggested as AD biomarkers.
CONCLUSIONS AND RELEVANCE To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.

• 出版日期2015-11