Portal de Periódicos da CAPES

Long runs of homozygosity are associated with Alzheimer’s disease

2021; Springer Nature; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41398-020-01145-1

2158-3188

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, Carla Abdelnour, N. Aguilera, Emilio Alarcón‐Martín, Montserrat Alegret, Alba Benaque, Merçé Boada, Mar Buendía, Pilar Cañabate, Ángel Carracedo, Arturo Corbatón Anchuelo, Itziar de Rojas, S. Diego, Ana Espinosa, A. Gailhajenet, Pablo García‐González, Saulo Gil, M. Guitart, Antonio González‐Pérez, Isabel Hernández, Marta Ibarria, A. Lafuente, Juan Macı́as, Olalla Maroñas, Eden R. Martin, María Teresa González Martínez, Marta Marquié, Ana Mauleón, Gemma C. Monté, Laura Montrreal, Sonia Moreno‐Grau, M. Moreno, Adelina Orellana, Gemma Ortega, A. Pancho, E. Pelejà, Alba Pérez‐Cordón, Juan A. Pineda, Sílvia Preckler, Inés Quintela, Luís Miguel Real, Octavio Rodríguez‐Gómez, Maiteé Rosende‐Roca, Agustı́n Ruiz, Susana Ruiz, María Eugenia Sáez, Ángela Sanabria, Miguel A. Santos‐Santos, Manuel Serrano‐Ríos, Óscar Sotolongo‐Grau, Lluís Tárraga, Sergi Valero, 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, Isabel Hernández, S. Hevilla, Silvia Jesús, M. A. Labrador Espinosa, Carmen Lage, Agustina Legaz, Alberto Lleó, Adolfo López de Munain, Sara López‐García, Diego Macías Saint-Gerons, Salvadora Manzanares, M. Marín, Juan Marín-Muñoz, Teresa J. Marin, Marta Marquié, A. Martín-Montes, B. Martínez, Carmen Martı́nez, Verónica S. Martínez, Pablo Martínez-Lage Álvarez, Miguel Medina, Maite Mendióroz, Manuel Menéndez‐González, Pablo Mir, José Luís Molinuevo, Laura Montrreal, Sonia Moreno‐Grau, Adelina Orellana, Ana Belén Pastor, Pau Pástor, Jordi Pérez‐Tur, María Teresa Periñán, Gerard Piñol‐Ripoll, Alberto Rábano, Diego Real de Asúa, S. Rodrigo, Eloy Rodríguez‐Rodríguez, José Luís Royo, Agustı́n Ruiz, R. Sanchez del Valle Díaz, Pascual Sánchez‐Juan, I. Sastre, Óscar Sotolongo‐Grau, Lluís Tárraga, Sergi Valero, Mário Vicente, L. Vivancos, Marta Marquié, Sergi Valero, Alba Benaque, Jordi Clarimón, María J. Bullido, Guillermo García‐Ribas, Pau Pástor, Pascual Sánchez‐Juan, Victoria Álvarez, Gerard Piñol‐Ripoll, José María García‐Alberca, José Luís Royo, Emilio Franco‐Macías, Pablo Mir, Miguel Calero, Miguel Medina, Alberto Rábano, Jesús Ávila, Carmen Antúnez, Luís Miguel Real, Adelina Orellana, Ángel Carracedo, María Eugenia Sáez, Lluís Tárraga, Merçé Boada, Carlos Cruchaga, Agustı́n Ruiz,

Bioinformatics and Genomic Networks

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.