FinnGen provides genetic insights from a well-phenotyped isolated population
FinnGen предоставляет генетические сведения о хорошо фенотипированном изолированном населении
2023-01-18
SCID: 54.1/8kg3wj9v
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FinnGenfine-mapping of coding variantsgenome-wide association study (GWAS)low-frequency variants (0.1%–5% MAF)population isolate
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Abstract (AI)
Abstract 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 explored 1,2 . 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.
Key Findings
1
A GWAS of 1,932 diseases found 2,733 genome-wide significant associations at 2,496 independent loci, including 893 phenome-wide significant (PWS) associations (P < 2.6 × 10⁻¹¹).
2
Analysis of 15 diseases and meta-analyses with Estonian and UK biobank data identified 30 novel associations, primarily low-frequency variants enriched in Finland.
3
Bottlenecked (isolated) populations like Finland are powerful for discovering low-frequency, higher-impact variants that provide biological entry points into common diseases.
4
Fine-mapping implicated 148 coding variants (73 PWS) associated with 83 end points (42 PWS).
5
FinnGen analysed genetic and national health register data from 224,737 Finnish participants (part of a 500,000 target cohort) enriched for disease end points.
6
Ninety-one implicated variants (47 PWS) had allele frequency <5% in non-Finnish Europeans; 62 of these (32 PWS) were enriched more than twofold in Finland.
Research Object
FinnGen cohort of 224,737 well-phenotyped Finnish participants (population isolate) and linked national health register and biobank genomic data
Research Subject
Genetic associations of low-frequency (0.1%–5%) and enriched variants with common diseases across 1,932 phenotypes, including discovery of novel genome-wide significant loci, fine-mapped coding variants, and population enrichment effects in a bottlenecked population
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2023-01-18
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