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.

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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.

In 1997, the National Institutes of Health convened a Consensus Development Conference on Cystic Fibrosis (CF). 1 The Consensus Conference recommended that genetic screening for CF mutations should be offered to identify carriers among adults with a positive family history of CF, partners of individuals with CF, couples currently planning a pregnancy, and couples seeking prenatal care. A second NIH-sponsored conference that focused on the implementation of the Consensus Conference recommendations was held in 1998. 2 Shortly thereafter, the American College of Medical Genetics (ACMG) and the American College of Obstetricians and Gynecologists (ACOG), in conjunction with the National Human Genome Research Institute, formed a Steering Committee to coordinate the implementation of population-based CF carrier screening and to develop "Clinical and Laboratory Provider Guidelines" for (1) provider education; (2) laboratory testing, interpretation, and genetic counseling; and (3) patient education and informed consent. The ACMG charged the Accreditation of Genetic Services Committee, chaired by Dr. Robert Desnick, to establish a Subcommittee on Cystic Fibrosis Carrier Screening (henceforth the "Committee") to develop recommendations and guidelines for optimal laboratory testing, interpretation, and counseling. The Subcommittee, cochaired by Drs. Wayne Grody and Garry Cutting, met twice yearly since October 1998. The issues considered by the Committee included (1) the target population to be screened (universal vs. limited to certain high-risk ethnic groups); (2) the screening model to be used (couple-based vs. sequential); (3) criteria for and selection of the standard mutation testing panel; (4) potential value and use of an extended testing panel with additional mutations; (5) whether to test for mutations and variants associated with mild or nonclassical phenotypes (such as congenital bilateral absence of the vas deferens); (6) test interpretation, reporting, and genetic counseling; and (7) laboratory quality assurance. The recommendations detailed here have been incorporated into a joint ACMG/ACOG/NIH Steering Committee document entitled "Preconceptual and Prenatal Carrier Screening for Cystic Fibrosis" which will be widely distributed. This document also will include guidelines for providers, patient education, and informed consent. Patient education materials will include two pamphlets, entitled "Cystic Fibrosis Carrier Testing.. . The Decision is Yours" and "Cystic Fibrosis Testing: What Happens if Both My Partner and I are Carriers?" It is important to note that these guidelines were prepared for population CF carrier screening and that different testing and counseling strategies would be employed for the identification of the mutation(s) in patients diagnosed with CF or in relatives of CF patients. Such diagnostic and prenatal mutation analyses should be referred to a genetics center for appropriate testing and counseling.

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by a deficiency of survival motor neuron (SMN) due to mutations in the SMN1 gene. In this study, an adeno-associated virus (AAV) vector expressing human SMN (AAV8-hSMN) was injected at birth into the CNS of mice modeling SMA. Western blot analysis showed that these injections resulted in widespread expression of SMN throughout the spinal cord, and this translated into robust improvement in skeletal muscle physiology, including increased myofiber size and improved neuromuscular junction architecture. Treated mice also displayed substantial improvements on behavioral tests of muscle strength, coordination, and locomotion, indicating that the neuromuscular junction was functional. Treatment with AAV8-hSMN increased the median life span of mice with SMA-like disease to 50 days compared with 15 days for untreated controls. Moreover, injecting mice with SMA-like disease with a human SMN-expressing self-complementary AAV vector -a vector that leads to earlier onset of gene expression compared with standard AAV vectors -led to improved efficacy of gene therapy, including a substantial extension in median survival to 157 days. These data indicate that CNS-directed, AAV-mediated SMN augmentation is highly efficacious in addressing both neuronal and muscular pathologies in a severe mouse model of SMA.