Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/12684
Long runs of homozygosity are associated with Alzheimer's disease.
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 | 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 ISCIII | 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
Transl Psychiatry . 2021 Feb 24;11(1):142
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.
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