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

Mitja Kurki ,Päivi Vieira,Satu Korpi-Heikkilä,Minna Männikkö,Eija Hämäläinen,Olli Pietiläinen,Jarmo Körkkö,Elisa Rahikkala,Outi Kuismin,Sini Kerminen,Elmo Saarentaus,Minna Holm ,Jaana Suvisaari,Riikka Keski‐Filppula ,Merja Rauhala,Aki S Havulinna,Matti Pirinen,Veikko Salomaa,Markku Peltonen,Padraigh Gormley ,Mark J Daly,Dennis Lal,Jukka S Moilanen,Heli Helander,Jonna Komulainen‐Ebrahim ,Aarno Palotie

doi:10.1038/s41467-018-08262-y

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.

Highlights

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
We studied the contribution of SNVs and INDELs, copy number variations (CNVs), and of a genome-wide common variant polygenic load
We identified a likely pathogenic variant in genes known to be associated with ID in 18% of the cases for which both exome and CNV data were available (Fig. 5a), explaining an estimated 4.2% of the heritability (Fig. 7)

Summary

Introduction

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. 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). Finland is a well-characterized genetic isolate where the small size of the founder population, subsequent bottleneck effects, and genetic drift have caused an enrichment of some rare and low-frequency variants as compared to other

Methods

Results

Conclusion