Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.

Population isolates such as Finland provide benefits in genetic studies because the allelic spectrum of damaging alleles in any gene is often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%), which survived the founding bottleneck, as opposed to being distributed over a much larger number of ultra--rare variants. While this advantage is well-- established in Mendelian genetics, its value in common disease genetics has been less explored. FinnGen aims to study the genome and national health register data of 500,000 Finns, already reaching 224,737 genotyped and phenotyped participants. Given the relatively high median age of participants (63 years) and dominance of hospital-based recruitment, FinnGen is enriched for many disease endpoints often underrepresented in population-based studies (e.g., rarer immune-mediated diseases and late onset degenerative and ophthalmologic endpoints). We report here a genome-wide association study (GWAS) of 1,932 clinical endpoints defined from nationwide health registries. We identify genome--wide significant associations at 2,491 independent loci. Among these, finemapping implicates 148 putatively causal coding variants associated with 202 endpoints, 104 with low allele frequency (AF<10%) of which 62 were over two-fold enriched in Finland.We studied a benchmark set of 15 diseases that had previously been investigated in large genome-wide association studies. FinnGen discovery analyses were meta-analysed in Estonian and UK biobanks. We identify 30 novel associations, primarily low-frequency variants strongly enriched, in or specific to, the Finnish population and Uralic language family neighbors in Estonia and Russia.These findings demonstrate the power of bottlenecked populations to find unique entry points into the biology of common diseases through low-frequency, high impact variants. Such high impact variants have a potential to contribute to medical translation including drug discovery.

The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear.OBJECTIVE To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency Յ0.05%; size Ն250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTSThe population biobank of Estonia contains 52 000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health-and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURESPhenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTSOf the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, Յ0.05%; Ն250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (Ն250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (Ն1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom.CONCLUSIONS AND RELEVANCE Known pathogenic CNVs in unselected, but assumed to be healthy, adult popu...

In the human genome, genetic sequences that differ in the numbers of copies, or so-called copy number variations (CNVs), can be associated with intellectual disability and developmental delay. Large, recurrent CNVs are particularly associated with these complex disorders. Previous studies of the effects of large CNVs have generally pediatric subjects with clinical disordered, and there are more limited data on the population frequency in asymptomatic adults. This study looks at the adult carriers of CNVs and aims to assess the consequences of rare CNVs.The study utilized the Estonian Genome Center at the University of Tartu, which includes 52,000 participants. For CVanalysis, genomic DNA from 6819 individuals was used for the discovery cohort and 1058 for the replication cohorts. The phenotypes of CNV carriers were compared with phenotypes in the general population. A third "high-functioning replication cohort" of 933, as well as a UK cohort of 5218, a US cohort of 2390, and an Italian cohort of 451, was used for replication for further analysis regarding education attainment.In the Estonian cohort, 56 of 7877 participants were identified as carriers of known autosomal genomic disorders. Of the 6819 individuals in the discovery cohort, 509 were identified as duplication carriers, and 216 were identified as deletion carriers. Of the 216 deletion carriers of at least 250 kb, 11 (5.1%) had an intellectual disability (odds ratio [OR], 3.16%; 95% confidence interval [CI], 1.51-5.98; P = 1.5E−03). Of 102 carrier with a duplication of at least 1 Mb, 6 (5.9%) had an intellectual disability (OR, 3.67; 95% CI, 1.29-8.54; P = 0.008). This was compared with 114 in the Estonian cohort of 6819 (1.7%); 3.2% of rare CNV carriers were diagnosed with intellectual disabilities, whereas 1.7% of the Estonian cohort was diagnosed with intellectual disability (OR, 1.93; 95% CI, 1.17-3.06; P = 0.007). Larger CNV size was shown to be associated with frequency of intellectual disability; 33.5% of deletion carriers (OR, 1.48; 95% CI, 1.12-1.95; P = 0.005) and 39.1% of duplication carriers (OR; 1.89; 95% CI, 1.27-2.8; P = 1.6e−03) did not graduate from high school.Evidence supporting an association between prevalence of intellectual disability and carrier status was found. Analysis of the Italian, United States, and United Kingdom cohorts supported the association between rare CNVs and lower educational attainment, but further replication of the study's findings is needed.