Long runs of homozygosity are associated with Alzheimer’s disease
Sonia Moreno–Grau, María Victoria Fernández, Itziar de Rojas, Pablo García‐González, Isabel Hernández, Fabiana Farias, John Budde, Inés Quintela, Laura Madrid, Antonio González‐Pérez, Laura Montrreal, Emilio Alarcón‐Martín, Montserrat Alegret, Olalla Maroñas, Juan A. Pineda, Juan Macı́as, The GR@ACE study group, Carla Abdelnour, N. Aguilera, Emilio Alarcón‐Martín, Montserrat Alegret, Alba Benaque, Merçé Boada, Mar Buendía, Pilar Cañabate, Ãngel Carracedo, A. Corbatón, Itziar de Rojas, S. Diego, Ana Espinosa, A. Gailhajenet, P. García González, Saulo Gil, M. Guitart, Antonio González‐Pérez, I. Hernández, Marta Ibarria, A. Lafuente, Juan Macı́as, Olalla Maroñas, Eden R. Martin, María Teresa González Martínez, M. Marquié, Ana Mauleón, Gemma C. Monté, Laura Montrreal, Sonia Moreno–Grau, M. Moreno, Adelina Orellana, Gemma Ortega, Ana Pancho, E. Pelejà, Alba Pérez‐Cordón, Juan A. Pineda, Sílvia Preckler, Inés Quintela, Luís Miguel Real, Octavio Rodríguez‐Gómez, Maitée Rosende‐Roca, A. Ruiz, Susana Ruiz, María Eugenia Sáez, Ángela Sanabria, Miguel Santos‐Santos, Manuel Serrano‐Ríos, Óscar Sotolongo‐Grau, O. Sotolongo-Grau, L. Tárraga, Liliana Vargas, Astrid Adarmes‐Gómez, Emilio Alarcón‐Martín, Ignacio Álvarez, Victoria Álvarez, G. Amer-Ferrer, M. Antequera, Carmen Antúnez, Miquel Baquero, M. Bernal, Rafael Blesa, Merçé Boada, Dolores Buiza‐Rueda, María J. Bullido, J A Burguera, Miguel Calero, F. Carrillo, Mario Carrión‐Claro, M. J. Casajeros, Jordi Clarimón, J. M. Cruz-Gamero, Marian M. de Pancorbo, Itziar de Rojas, Teodoro del Ser, Mónica Díez-Fairén, Juan Fortea, Emilio Franco, Ana Frank, José María García‐Alberca, S. García Madrona, Guillermo García‐Ribas, Pilar Gómez‐Garre
Abstract
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.