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.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder that is the leading cause of dementia worldwide[1].AD presents a strong genetic component
4-Analyses 4a-Association analysis between homozygosity parameters and AD risk To assess the quality of the data in each individual study, we explored sample distribution for each of four homozygosity parameters: number of ROHs (NROH), sum of ROH (SROH), average ROH length (AVROH), and FROH
runs of homozygosity (ROH) parameters are associated with AD risk We examined the typical characteristics of the four
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder that is the leading cause of dementia worldwide[1].AD presents a strong genetic component. Autosomal dominant mutations have been linked to familial early onset AD (EOAD) (
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