Extended Kindred With Recessive Late-Onset Alzheimer Disease Maps to Locus 8p22-p21.2

Abstract

Late-onset Alzheimer disease (LOAD) is a complex genetic disorder. Although genes involved in early-onset forms were discovered more than a decade ago, LOAD research has only been able to point out small effect loci, with the exception of APOE. We mapped the gene predisposing to LOAD in an extended inbred family coming from a genetically isolated region (24 sampled individuals, 12 of whom are affected), completing a genome-wide screen with an Affymetrix10 K single nucleotide polymorphism microarray. Genotyping results were evaluated under model-dependent (dominant and recessive) and model-free analysis. We obtained a maximum nonparametric linkage score of 3.24 (P=0.00006) on chromosome 8p22-p21.2. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) under a recessive model (HLOD=3.04). When we compared the results of the model-dependent analysis, a higher score was obtained in the recessive model (3.04) than in the dominant model (1.0). This is a new locus identified in LOAD, in chromosome 8p22-p21.2 and encompassing several candidate genes, among them CLU and PPP3CC that were excluded by sequencing. The finding of a recessive model of inheritance, consistent with the assumption of inbreeding as a morbidity factor in this population, supports the notion of a role of recessive genes in LOAD.

Insight into the genetic etiology of Alzheimer's disease: A comprehensive review of the role of rare variants

“…Additionally, genomewide linkage analysis performed in an extended recessive LOAD family identified a linked region on chromosome 8p22-p21.2. 83 More than 50 genes are included in the linked region and therefore, further analysis of these genes is necessary (e.g., by means of whole-genome sequencing in the LOAD family). 83 To identify additional novel loci harboring AD-associated recessive variants, several studies investigated extended runs of homozygosity (ROHs) in case-control cohorts of different ethnic backgrounds.…”

“…83 More than 50 genes are included in the linked region and therefore, further analysis of these genes is necessary (e.g., by means of whole-genome sequencing in the LOAD family). 83 To identify additional novel loci harboring AD-associated recessive variants, several studies investigated extended runs of homozygosity (ROHs) in case-control cohorts of different ethnic backgrounds. [84][85][86][87][88][89] One study performed ROH mapping in 837 LOAD and 550 controls from Northern European and Northern American ancestry and identified excess ROHs in cases versus controls, with the most significant LOAD associated ROH on chromosome 8p11.23.…”

“…Replication of these findings in larger cohorts is necessary to fully comprehend their contribution to the etiology of AD. Additionally, genome‐wide linkage analysis performed in an extended recessive LOAD family identified a linked region on chromosome 8p22‐p21.2 83 . More than 50 genes are included in the linked region and therefore, further analysis of these genes is necessary (e.g., by means of whole‐genome sequencing in the LOAD family) 83 …”

Genetics of Alzheimer's Disease

“…We are currently applying exome sequencing to follow up on these results and pinpoint the mutation causing AD in this family. Other AD families presenting with apparent autosomal recessive patterns of inheritance are starting to be described in the literature and we expect the study of recessive alleles in AD to have significant results in the near future [33].…”