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. 2015 Nov;72(11):1313-23.
doi: 10.1001/jamaneurol.2015.1700.

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

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Free PMC article

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

Mahdi Ghani et al. JAMA Neurol. .
Free PMC article

Abstract

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 raw or 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 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses.

Results: The African American cohort had a low degree 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 2 Mb (P = .004) or greater than 3 Mb (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 genes common for 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 >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% 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 which were 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.

Figures

Figure 1
Figure 1. Significant Results Obtained by Analyses of Consensus Regions
Consensus regions are indicated by red bars containing white arrowheads. A, The consensus region detected in the Alzheimer’s Disease Genetics Consortium (ADGC) data set contains the SH3D19 and RPS3A genes intersected by runs of homozygosity greater than 2 Mb in 7 cases (samples 10AD24322, 10AD30747, 11AD35799, 11AD35549, 10AD32217, 10AD32219, and 11AD35543) and no control individuals. B, The consensus region detected in the Chicago Health and Aging Project (CHAP)–Indianapolis Ibadan Dementia Study (IIDS) data set contains the STOML1, PML, GOLGA6A, and ISLR2 genes intersected by runs of homozygosity greater than 1 Mb in 5 cases (samples PT-J6K8_796, PT-J6L9_937, PT-28ZI_899514246, PT-9X4V_537994104, and PT-J7BC_5951) and no control individuals.
Figure 2
Figure 2. Significant Results Obtained by Gene-Based Analyses of the Chicago Health and Aging Project (CHAP)–Indianapolis Ibadan Dementia Study (IIDS) Data Set
The top section shows the runs of homozygosity (ROHs) greater than 3 Mb on chromosome 3 among cases (n = 279) and control individuals (n = 1367). Owing to an unbalanced distribution of cases and control individuals, fewer ROHs were observed among cases compared with control individuals, except at the Chr3p21.31 locus (section within the dashed lines), which was affected by ROHs greater than 3 Mb significantly more frequently in cases (2.9%, red bars) compared with control individuals (0.4%, blue bars). The middle section shows 2 down-brackets pointing to the significantly overlapped genes. The bottom section shows the linkage disequilibrium structure of the Chr3:46500000-52500000/hg18 region estimated based on control genotypes from the CHAP-IIDS data set. tRNA indicates transfer ribonucleic acid; UCSC, University of California–Santa Cruz.
Figure 3
Figure 3. Significant Results Obtained by Gene-Based Analyses of the Entire Data Set
The CLDN17 gene was intersected by runs of homozygosity (ROH) in 11 cases (red bars) but no control individuals (blue bar). CCDS indicates consensus coding sequence; tRNA, transfer ribonucleic acid; UCSC, University of California–Santa Cruz.

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