Long runs of homozygosity are associated with Alzheimer’s disease

Abstract

Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer’s disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [βAVROH (CI 95%) = 0.070 (0.037–0.104); P = 3.91 × 10−5; βFROH (CI95%) = 0.043 (0.009–0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10−16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10−4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.

Discovery of runs-of-homozygosity diplotype clusters and their associations with diseases in UK Biobank

“…Our objective is also to select clusters with a sufficiently large number of individuals to correlate them with phenotypes. It is worth noting that in previous studies, a minimum cut-off of 100 individuals was commonly used ( Lencz et al, 2007 ; Christofidou et al, 2015 ; Moreno-Grau et al, 2021 ). On average ~18% of sites are heterozygous, and thus for a pair of 100 sites genotype sequences, there is a very small probability that they will be mapped to the same compressed haplotype.…”

Genotypic and phenotypic consequences of domestication in dogs

“…In humans, ROH are associated with numerous complex disease and non-disease phenotypes (Clark et al 2019; Johnson, Evans, and Keller 2018; Moreno-Grau et al 2021; Keller et al 2012; Bacolod et al 2008), and in dogs ROH have been associated with disease phenotypes (Mooney, Yohannes, and Lohmueller 2021; Sams and Boyko 2019; Boyko 2011). Previous studies have shown the influence of genetic variants in different quantitative traits such as leg length, wrinkled skin, coat color, hair length, and skeletal shape (Sutter et al 2007; Boyko et al 2010; Parker et al 2009; Cadieu et al 2009; Candille et al 2007).…”

Dementia-related genetic variants in an Italian population of early-onset Alzheimer’s disease

“…It is also likely that variants specific to individual populations, and thus difficult to detect with genome-wide ass1ociation study (GWAS) approaches unless the population is homogenous, may explain at least a portion of the missing heritability of EOAD. In addition, other inheritance patterns should be considered, e.g., autosomal recessive loci might cause EOAD ( Moreno-Grau et al, 2021 ).…”