2024-03-28T16:26:08Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/126842023-10-05T06:18:48Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_2137com_20.500.12105_2052col_20.500.12105_16990col_20.500.12105_16986col_20.500.12105_16972col_20.500.12105_16970col_20.500.12105_16966col_20.500.12105_16963col_20.500.12105_16958col_20.500.12105_2138
00925njm 22002777a 4500
dc
Moreno-Grau, Sonia
author
Fernández, Maria Victoria
author
de Rojas, Itziar
author
Garcia-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
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Marquié, Marta
author
Valero, Sergi
author
Benaque, Alba
author
Clarimón, Jordi
author
Bullido, Maria Jesus
author
García-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
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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
http://hdl.handle.net/20.500.12105/12684
33627629
10.1038/s41398-020-01145-1
2158-3188
Translational psychiatry
Long runs of homozygosity are associated with Alzheimer's disease.