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

Publication ,  Journal Article
Ghani, M; Reitz, C; Cheng, R; Vardarajan, BN; Jun, G; Sato, C; Naj, A; Rajbhandary, R; Wang, L-S; Valladares, O; Lin, C-F; Larson, EB; Raj, T ...
Published in: JAMA Neurol
November 2015

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.

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Published In

JAMA Neurol

DOI

EISSN

2168-6157

Publication Date

November 2015

Volume

72

Issue

11

Start / End Page

1313 / 1323

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Indiana
  • Humans
  • Homozygote
  • Genome-Wide Association Study
  • Genes, Recessive
  • Chicago
  • Case-Control Studies
  • Black or African American
  • Alzheimer Disease
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Ghani, M., Reitz, C., Cheng, R., Vardarajan, B. N., Jun, G., Sato, C., … Alzheimer’s Disease Genetics Consortium, . (2015). Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals. JAMA Neurol, 72(11), 1313–1323. https://doi.org/10.1001/jamaneurol.2015.1700
Ghani, Mahdi, Christiane Reitz, Rong Cheng, Badri Narayan Vardarajan, Gyungah Jun, Christine Sato, Adam Naj, et al. “Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals.JAMA Neurol 72, no. 11 (November 2015): 1313–23. https://doi.org/10.1001/jamaneurol.2015.1700.
Ghani M, Reitz C, Cheng R, Vardarajan BN, Jun G, Sato C, et al. Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals. JAMA Neurol. 2015 Nov;72(11):1313–23.
Ghani, Mahdi, et al. “Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals.JAMA Neurol, vol. 72, no. 11, Nov. 2015, pp. 1313–23. Pubmed, doi:10.1001/jamaneurol.2015.1700.
Ghani M, Reitz C, Cheng R, Vardarajan BN, Jun G, Sato C, Naj A, Rajbhandary R, Wang L-S, Valladares O, Lin C-F, Larson EB, Graff-Radford NR, Evans D, De Jager PL, Crane PK, Buxbaum JD, Murrell JR, Raj T, Ertekin-Taner N, Logue M, Baldwin CT, Green RC, Barnes LL, Cantwell LB, Fallin MD, Go RCP, Griffith PA, Obisesan TO, Manly JJ, Lunetta KL, Kamboh MI, Lopez OL, Bennett DA, Hendrie H, Hall KS, Goate AM, Byrd GS, Kukull WA, Foroud TM, Haines JL, Farrer LA, Pericak-Vance MA, Lee JH, Schellenberg GD, St George-Hyslop P, Mayeux R, Rogaeva E, Alzheimer’s Disease Genetics Consortium. Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals. JAMA Neurol. 2015 Nov;72(11):1313–1323.

Published In

JAMA Neurol

DOI

EISSN

2168-6157

Publication Date

November 2015

Volume

72

Issue

11

Start / End Page

1313 / 1323

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Indiana
  • Humans
  • Homozygote
  • Genome-Wide Association Study
  • Genes, Recessive
  • Chicago
  • Case-Control Studies
  • Black or African American
  • Alzheimer Disease