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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; Abdelnour, C.; Aguilera, N.; Alarcón-Martín, E.; Alegret, M.; Benaque, A.; Boada, M.; Buendía, M.; Cañabate, P.; [...]

Long runs of homozygosity are associated with Alzheimer’s disease

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  • Medientyp: E-Artikel
  • Titel: Long runs of homozygosity are associated with Alzheimer’s disease
  • Beteiligte: 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; Abdelnour, C.; Aguilera, N.; Alarcón-Martín, E.; Alegret, M.; Benaque, A.; Boada, M.; Buendía, M.; Cañabate, P.; [...]
  • Erschienen: Springer Science and Business Media LLC, 2021
  • Erschienen in: Translational Psychiatry
  • Sprache: Englisch
  • DOI: 10.1038/s41398-020-01145-1
  • ISSN: 2158-3188
  • Schlagwörter: Biological Psychiatry ; Cellular and Molecular Neuroscience ; Psychiatry and Mental health
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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 [<jats:italic>β</jats:italic><jats:sub>AVROH</jats:sub> (CI 95%) = 0.070 (0.037–0.104); <jats:italic>P</jats:italic> = 3.91 × 10<jats:sup>−5</jats:sup>; <jats:italic>β</jats:italic><jats:sub>FROH</jats:sub> (CI95%) = 0.043 (0.009–0.076); <jats:italic>P</jats:italic> = 0.013]. ROHs increasing the risk of AD (OR &gt; 1) were significantly overrepresented compared to ROHs increasing protection (<jats:italic>p</jats:italic> &lt; 2.20 × 10<jats:sup>−16</jats:sup>). A significant ROH association with AD risk was detected upstream the <jats:italic>HS3ST1</jats:italic> locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), <jats:italic>p</jats:italic> value = 9.03 × 10<jats:sup>−4</jats:sup>), 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 (<jats:italic>N</jats:italic> = 1449). We detected a candidate marker, rs117458494, mapped in the <jats:italic>SPON1</jats:italic> 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.</jats:p>
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