In:
Translational Psychiatry, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2021-02-24)
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 [ β AVROH (CI 95%) = 0.070 (0.037–0.104); P = 3.91 × 10 −5 ; β FROH (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.
Type of Medium:
Online Resource
ISSN:
2158-3188
DOI:
10.1038/s41398-020-01145-1
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2021
detail.hit.zdb_id:
2609311-X
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