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The impact of rare protein coding genetic variation on adult cognitive function

2023; Nature Portfolio; Volume: 55; Issue: 6 Linguagem: Inglês

10.1038/s41588-023-01398-8

1546-1718

Chia‐Yen Chen, Ruoyu Tian, Tian Ge, Max Lam, Gabriela Sánchez-Andrade, Tarjinder Singh, Lea Urpa, Jimmy Z. Liu, Mark Sanderson, Christine Rowley, Holly Ironfield, Terry Fang, Aija Kyttälä, Amanda Elliott, Anders Kämpe, André Sourander, Annamari Tuulio‐Henriksson, Anssi Solismaa, Antti Tanskanen, Ari Ahola‐Olli, Arto Mustonen, Arttu Honkasalo, Asko Wegelius, Atiqul Haq Mazumder, Auli Toivola, Benjamin M. Neale, Elina Hietala, Elmo Saarentaus, Erik Cederlöf, Erkki Isometsä, Heidi Taipale, Imre Västrik, Jaana Suvisaari, Jari Tiihonen, Jarmo Hietala, Johan Ahti, Jonne Lintunen, Jouko Lönnqvist, Juha Veijola, Julia Moghadampour, Jussi Niemi-Pynttäri, Kaisla Lahdensuo, Katja Häkkinen, Katriina Hakakari, Kimmo Suokas, Marjo Taivalantti, Markku Lähteenvuo, Martta Kerkelä, Minna Torniainen‐Holm, Nina Lindberg, Noora Ristiluoma, Olli Kampman, Olli Pietiläinen, Risto Kajanne, Sari Lång-Tonteri, Solja Niemelä, Steven E. Hyman, Susanna Rask, Teemu Männynsalo, Tiina Paunio, Tuomas Jukuri, Tuomo Kiiskinen, Tuula Kieseppä, Ville Mäkipelto, Willehard Haaki, Zuzanna Misiewicz, Mitja Kurki, Jarmo Körkkö, Jukka S. Moilanen, Outi Kuismin, Mark J. Daly, Aarno Palotie, Ellen Tsai, Hailiang Huang, Matthew E. Hurles, Sebastian S. Gerety, Todd Lencz, Heiko Runz,

Bioinformatics and Genomic Networks

Abstract Compelling 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.