The impact of rare protein coding genetic variation on adult cognitive function
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Published:2023-05-25
Issue:6
Volume:55
Page:927-938
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ISSN:1061-4036
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Container-title:Nature Genetics
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language:en
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Short-container-title:Nat Genet
Author:
Chen Chia-YenORCID, Tian Ruoyu, Ge Tian, Lam MaxORCID, Sanchez-Andrade Gabriela, Singh TarjinderORCID, Urpa Lea, Liu Jimmy Z.ORCID, Sanderson Mark, Rowley Christine, Ironfield Holly, Fang Terry, Kyttälä Aija, Elliott Amanda, Kämpe Anders, Sourander Andre, Tuulio-Henriksson Annamari, Solismaa Anssi, Tanskanen Antti, Ahola-Olli Ari, Mustonen Arto, Honkasalo Arttu, Wegelius Asko, Mazumder Atiqul, Toivola Auli, Neale Benjamin, Hietala Elina, Saarentaus Elmo, Cederlöf Erik, Isometsä Erkki, Taipale Heidi, Västrik Imre, Suvisaari Jaana, Tiihonen Jari, Hietala Jarmo, Ahti Johan, Lintunen Jonne, Lönnqvist Jouko, Veijola Juha, Moghadampour Julia, Niemi-Pynttäri Jussi, Lahdensuo Kaisla, Häkkinen Katja, Hakakari Katriina, Suokas Kimmo, Taivalantti Marjo, Lähteenvuo Markku, Kerkelä Martta, Holm Minna, Lindberg Nina, Ristiluoma Noora, Kampman Olli, Pietiläinen Olli, Kajanne Risto, Lång-Tonteri Sari, Niemelä Solja, Hyman Steven E., Rask Susanna, Männynsalo Teemu, Paunio Tiina, Jukuri Tuomas, Kiiskinen Tuomo, Kieseppä Tuula, Mäkipelto Ville, Haaki Willehard, Misiewicz Zuzanna, Kurki Mitja I., Körkkö Jarmo, Moilanen Jukka, Kuismin Outi, Daly Mark, Palotie AarnoORCID, Tsai Ellen A.ORCID, Huang HailiangORCID, Hurles Matthew E.ORCID, Gerety Sebastian S.ORCID, Lencz ToddORCID, Runz HeikoORCID, , ,
Abstract
AbstractCompelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population (n = 485,930). We identify eight genes (ADGRB2, KDM5B, GIGYF1, ANKRD12, SLC8A1, RC3H2, CACNA1A and BCAS3) that are associated with adult cognitive function through rare coding variants with large effects. Rare genetic architecture for cognitive function partially overlaps with that of neurodevelopmental disorders. In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population.
Publisher
Springer Science and Business Media LLC
Reference86 articles.
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