Contribution of rare and common variants to intellectual disability in a sub-isolate of Northern Finland

Mitja I. Kurki, Elmo Saarentaus, Olli Pietiläinen, Padhraig Gormley, Dennis Lal, Sini Kerminen, Minna Torniainen-Holm, Eija Hämäläinen, Elisa Rahikkala, Riikka Keski-Filppula, Merja Rauhala, Satu Korpi-Heikkilä, Jonna Komulainen–Ebrahim, Heli Helander, Päivi Vieira, Minna Männikkö, Markku Peltonen, Aki S. Havulinna, Veikko Salomaa, Matti Pirinen, Jaana Suvisaari, Jukka S. Moilanen, Jarmo Körkkö, Outi Kuismin, Mark J. Daly and Aarno Palotie ()
Additional contact information
Mitja I. Kurki: Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston
Elmo Saarentaus: University of Helsinki
Olli Pietiläinen: The Broad Institute of MIT and Harvard
Padhraig Gormley: Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston
Dennis Lal: Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston
Sini Kerminen: University of Helsinki
Minna Torniainen-Holm: University of Helsinki
Eija Hämäläinen: University of Helsinki
Elisa Rahikkala: University of Oulu
Riikka Keski-Filppula: University of Oulu
Merja Rauhala: Northern Ostrobothnia Hospital District, Center for Intellectual Disability Care
Satu Korpi-Heikkilä: Northern Ostrobothnia Hospital District, Center for Intellectual Disability Care
Jonna Komulainen–Ebrahim: Oulu University Hospital, Medical Research Center Oulu, University of Oulu
Heli Helander: Oulu University Hospital, Medical Research Center Oulu, University of Oulu
Päivi Vieira: Oulu University Hospital, Medical Research Center Oulu, University of Oulu
Minna Männikkö: University of Oulu
Markku Peltonen: National Institute for Health and Welfare
Aki S. Havulinna: University of Helsinki
Veikko Salomaa: National Institute for Health and Welfare
Matti Pirinen: University of Helsinki
Jaana Suvisaari: National Institute for Health and Welfare
Jukka S. Moilanen: University of Oulu
Jarmo Körkkö: Northern Ostrobothnia Hospital District, Center for Intellectual Disability Care
Outi Kuismin: University of Helsinki
Mark J. Daly: Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston
Aarno Palotie: Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract The contribution of de novo variants in severe intellectual disability (ID) has been extensively studied whereas the genetics of mild ID has been less characterized. To elucidate the genetics of milder ID we studied 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. Using exome sequencing, we show that rare damaging variants in known ID genes are observed significantly more often in severe (27%) than in mild ID (13%) patients. We further observe a significant enrichment of functional variants in genes not yet associated with ID (OR: 2.1). We show that a common variant polygenic risk significantly contributes to ID. The heritability explained by polygenic risk score is the highest for educational attainment (EDU) in mild ID (2.2%) but lower for more severe ID (0.6%). Finally, we identify a Finland enriched homozygote variant in the CRADD ID associated gene.

Date: 2019
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DOI: 10.1038/s41467-018-08262-y

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