Long runs of homozygosity are associated with Alzheimer’s disease
Authors: Moreno-Grau Sonia , Fernández Maria Victoria , de Rojas Itziar , Garcia-González Pablo , Hernández Isabel , Farias Fabiana , Budde John P. , Quintela Inés , Madrid Laura , González-Pérez Antonio , Montrreal Laura , Alarcón-Martín Emilio , Alegret Montserrat , Maroñas Olalla , Pineda Juan Antonio , Macías Juan ,   The GR@ACE study group, Abdelnour C. , Aguilera N. , Alarcón-Martín E. , Alegret M. , Benaque A. , Boada M. , Buendía M. , Cañabate P. , Carracedo A. , Corbatón A. , de Rojas I. , Diego S. , Espinosa A. , Gailhajenet A. , García González P. , Gil S. , Guitart M. , González Pérez A. , Hernández I. , Ibarria M. , Lafuente A. , Macías J. , Maroñas O. , Martín E. , Martínez M. T. , Marquié M. , Mauleón A. , Monté-Rubio G. , Montrreal L. , Moreno-Grau S. , Moreno M. , Orellana A. , Ortega G. , Pancho A. , Pelejà E. , Pérez-Cordon A. , Pineda J. A. , Preckler S. , Quintela I. , Real L. M. , Rodríguez-Gómez O. , Rosende-Roca M. , Ruiz A. , Ruiz S. , Sáez M. E. , Sanabria A. , Santos-Santos M. A. , Serrano-Ríos M. , Sotolongo-Grau O. , Tárraga L. , Valero S. , Vargas L. ,   DEGESCO consortium, Adarmes-Gómez A. D. , Alarcón-Martín E. , Álvarez I. , Álvarez V. , Amer-Ferrer G. , Antequera M. , Antúnez C. , Baquero M. , Bernal M. , Blesa R. , Boada M. , Buiza-Rueda D. , Bullido M. J. , Burguera J. A. , Calero M. , Carrillo F. , Carrión-Claro M. , Casajeros M. J. , Clarimón J. , Cruz-Gamero J. M. , de Pancorbo M. M. , de Rojas I. , del Ser T. , Diez-Fairen M. , Fortea J. , Franco E. , Frank-García A. , García-Alberca J. M. , García Madrona S. , Garcia-Ribas G. , Gómez-Garre P. , Hernández I. , Hevilla S. , Jesús S. , Labrador Espinosa M. A. , Lage C. , Legaz A. , Lleó A. , López de Munáin A. , López-García S. , Macías D. , Manzanares S. , Marín M. , Marín-Muñoz J. , Marín T. , Marquié M. , Martín-Montes A. , Martínez B. , Martínez C. , Martínez V. , Martínez-Lage Álvarez P. , Medina M. , Mendioroz Iriarte M. , Menéndez-González M. , Mir P. , Molinuevo J. L. , Montrreal L. , Moreno-Grau S. , Orellana A. , Pastor A. B. , Pastor P. , Pérez-Tur J. , Periñán-Tocino T. , Piñol-Ripoll G. , Rábano A. , Real de Asúa D. , Rodrigo S. , Rodríguez-Rodríguez E. , Royo J. L. , Ruiz A. , Sanchez del Valle Díaz R. , Sánchez-Juan P. , Sastre I. , Sotolongo-Grau O. , Tárraga L. , Valero S. , Vicente M. P. , Vivancos L. , Marquié Marta , Valero Sergi , Benaque Alba , Clarimón Jordi , Bullido Maria Jesus , García-Ribas Guillermo , Pástor Pau , Sánchez-Juan Pascual , Álvarez Victoria , Piñol-Ripoll Gerard , García-Alberca Jose María , Royo José Luis , Franco-Macías Emilio , Mir Pablo , Calero Miguel , Medina Miguel , Rábano Alberto , Ávila Jesús , Antúnez Carmen , Real Luis Miguel , Orellana Adelina , Carracedo Ángel , Sáez María Eugenia , Tárraga Lluís , Boada Mercè , Cruchaga Carlos , Ruiz Agustín ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: February 2021

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.