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

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.

in all genes instead of only high pLI genes in C and D as MPC score incorporates regional missense constraint.   Read more at www.1000genomes.org/home.

AD_CASES_FINRISK
The FINRISK cohorts comprise the respondents of representative, cross-sectional population surveys that are carried out every 5 years since 1972, to assess the risk factors of chronic diseases (e.g. CVD, diabetes, obesity, cancer) and health behavior in the working age population, in 3-5 large study areas of Finland (Borodulin et al. Read more at www.nationalbiobanks.fi/index.php/studies2/34-adgen-study. Subsequently, the ADI-R was administered to autism families willing to continue to participate in the study. In a subset of the Finnish autism families a 96% concordance rate was observed between ICD-10 and ADI-R diagnosis of autism [20] making the Finnish autism families clinically comparable to international family sets used for genetic studies. One individual was included from each family in the case-control datasets, choosing the most severely affected individual (i.e. autism before Asperger Syndrome).

Botnia_T2D
The aims of Botnia cohort has been collected from the western coast of Finland in the Gulf of Bothnia for four different studies studying type 2 diabetes. The Botnia Study, started in 1990, is one of the largest diabetes family studies in the world. The initial family based Botnia study comprised of 11000 individuals as well as a prospective 10-year follow-up of 2800 individuals. The Botnia study also includes a population based study of 5200 individuals aged 18-75 with an ongoing 6-year follow-up study. A project aiming to cover all diabetic patients in the region has also been launched and includes at the moment more than 4000 individuals. The study includes individuals from about 4000 families (about 1000 independent trios) and extensive phenotype information is available for all study participants.

Eufam
EUFAM (European Study of Familial Dyslipidemias) study is a project aiming to reveal the molecular and genetic basis of familial combined hyperlipidemia (FCHL) and of familial low high-density cholesterol (HDL-C). The study cohort comprises of over 1500 family members from 140 Finnish families with premature coronary heart disease and with either FCHL or familial low HDL-C.

Finnish controls from a Swedish schizophrenia study
The study sought to identify the alleles, genes or gene networks that harbor rare coding variants of moderate or large effect on risk for schizophrenia by exomesequencing 5,079 individuals, selected from a Swedish sample of more than 11,000 individuals. Controls that were of Finnish ancestry were included in the current study. Purcell

FINRISK_IBD_CASE_CONTROLS
The FINRISK cohorts comprise the respondents of representative, cross-sectional population surveys that are carried out every 5 years since 1972, to assess the risk factors of chronic diseases (e.g. CVD, diabetes, obesity, cancer) and health behavior in the working age population, in 3-5 large study areas of Finland (Borodulin et al.

Fusion
The Finland-United States Investigation of NIDDM Genetics (FUSION) dataset is collected for localizing and identifying genetic variants that predispose to type 2 diabetes mellitus (T2D) or are responsible for variability in diabetes-related quantitative traits. The FUSION study sample includes approximately 800 families ascertained for sibling pairs affected with type 2 diabetes, including also parents, unaffected siblings, spouses and children in some cases; ~200 unrelated individuals with normal glucose tolerance at ages 65 and 70 years, with their spouses and children in some cases; and ~8400 mostly unrelated individuals including ~1700 type 2 diabetics selected from the D2D 2004, Finrisk 1987, Finrisk 2002, Health 2000, Action LADA, and Savitaipale Diabetes studies.

Migraine
The Finnish Migraine Family Study sample consists of migraine patients visiting headache clinics, from which extensive questionnaire data for headache and comorbid disorders has been collected.

NFBC
NFBC1966 is a birth cohort from two northern provinces of Oulu and Lapland. Mothers expected to give birth in the Oulu and Lapland in 1966 were invited to participate in the study, which was originally focused on factors affecting pre-term birth, low birth weight, and subsequent morbidity. The DNA was extracted from a blood sample drawn IN 31-year clinical examination.
We thank the late professor Paula Rantakallio (launch of NFBC1966), the participants in the 31yrs study and the NFBC project center.   (Paunio et al. 2001). Two samples were formed: isolate sample of families with at least one affected sibling from an isolated north-eastern region of Finland (Kuusamo) with a high lifetime risk of schizophrenia and families from the rest of Finland with at least two affected siblings (Hovatta et al. 1997).
The study protocol was accepted by the Ministry of Social Affairs and Health and by the ethics committees of the National Public Health Institute (currently, the National Institute for Health and Welfare) and the Hospital District of Helsinki and Uusimaa.