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00925njm 22002777a 4500 dc Moreno-Grau, Sonia author Fernández, Maria Victoria author de Rojas, Itziar author García-González, Pablo author Hernández, Isabel author Farias, Fabiana author Budde, John P author Quintela, Inés author Madrid, Laura author González-Pérez, Antonio author Montrreal, Laura author Alarcón-Martín, Emilio author Alegret, Montserrat author Maroñas, Olalla author Pineda, Juan Antonio author Macías, Juan author Marquié, Marta author Valero, Sergi author Benaque, Alba author Clarimón, Jordi author Bullido, María Jesús author Garcia-Ribas, Guillermo author Pástor, Pau author Sánchez-Juan, Pascual author Álvarez, Victoria author Piñol-Ripoll, Gerard author García-Alberca, Jose María author Royo, José Luis author Franco-Macías, Emilio author Mir, Pablo author Calero, Miguel author Medina, Miguel author Rábano, Alberto author Ávila, Jesús author Antúnez, Carmen author Real, Luis Miguel author Orellana, Adelina author Carracedo, Ángel author Sáez, María Eugenia author Tárraga, Lluís author Boada, Mercè author Cruchaga, Carlos author Ruiz, Agustín author 2021-02-24 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. Transl Psychiatry . 2021 Feb 24;11(1):142 10.1038/s41398-020-01145-1 2158-3188 Translational psychiatry 33627629 http://hdl.handle.net/20.500.12105/12684 Long runs of homozygosity are associated with Alzheimer's disease.