ABSTRACT Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of recent inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer’s disease (AD). However, the search for recessive variants has been poorly assessed to date. To investigate homozygosity in AD, we performed a fine-scale ROH analysis including 21,100 individuals from 10 cohorts of European ancestry (11,919 AD cases and 9,181 controls). We detected an increase of homozygosity in AD cases compared to controls [β FROH (CI95%) = 0.051 (0.023 – 0.078); P = 3.25 x 10 -4 ]. ROHs increasing the risk of AD (OR &gt; 1) were significantly overrepresented compared to ROHs increasing protection (p &lt; 2.20 x 10 -16 ). The top associated ROH with AD risk (β (CI95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 x 10 -4 ) was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), previously related to AD. Next, to construct a homozygosity map of AD cases, we selected ROHs shared by inbred AD cases extracted from an outbred population. We used whole-exome sequencing data from 1,449 individuals from the Knight-ADRC-NIA-LOAD (KANL) cohort to identify potential recessive variants in candidate ROHs. 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.

Autosomal Recessive Alzheimer’s disease (arAD): homozygosity mapping of genomic regions containing arAD loci