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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., (© 2023. The Author(s).)

The research of rare and devastating orphan diseases, such as idiopathic pulmonary fibrosis (IPF) has been limited by the rarity of the disease itself. The prognosis is poor-the prevalence of IPF is only approximately four times the incidence, limiting the recruitment of patients to trials and studies of the underlying biology. Global biobanking efforts can dramatically alter the future of IPF research. We describe a large-scale meta-analysis of IPF, with 8,492 patients and 1,355,819 population controls from 13 biobanks around the globe. Finally, we combine this meta-analysis with the largest available meta-analysis of IPF, reaching 11,160 patients and 1,364,410 population controls. We identify seven novel genome-wide significant loci, only one of which would have been identified if the analysis had been limited to European ancestry individuals. We observe notable pleiotropy across IPF susceptibility and severe COVID-19 infection and note an unexplained sex-heterogeneity effect at the strongest IPF locus MUC5B ., Competing Interests: A.S. and B.L.Y. are full-time employees of Genentech with stock and stock options in Roche. D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis and treatment of IPF. T.E.F. is a consultant to Eleven P15. R.G.J. has received research funding from Astra Zeneca, Biogen, Galecto, GlaxoSmithKline, RedX, and Pliant; consulting fees from Bristol Myers Squibb, Daewoong, Veracyte, Resolution Therapeutics, RedX, and Pliant; payment for lectures, presentations, speakers bureaus, manuscript writing or educational events from Chiesi, Roche, PatientMPower, and AstraZeneca; payment for Participation on a Data Safety Monitoring Board or Advisory Board from Boehringer Ingelheim, Galapagos, and Vicore, had a Leadership or fiduciary role in other board, society, committee or advocacy group (unpaid) in NuMedii and Action for Pulmonary Fibrosis; and is a trustee for Action for Pulmonary Fibrosis. L.V.W. has received research funding from GSK and Orion Pharma and consultancy for Galapagos. M.J.D. is a founder of Maze Therapeutics. J.T.K. and M.J.D. are members of the Pfizer Finland FinnGen Advisory Board., (© 2022 The Author(s).)