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.

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The lateral habenula (LHb) is a key brain region involved in the pathophysiology of depression. It is activated by stimuli associated with negative experiences and is involved in encoding aversive signals. Hyperactivity of LHb is found in both rodent models of depression and human patients with depression. However, little is known about the underlying molecular mechanisms. Here we show that, in LHb neurons, p11, a multifunctional protein implicated in depression, is significantly upregulated by chronic restraint stress. Knockdown of p11 expression in LHb alleviates the stress-induced depression-like behaviors. Moreover, chronic restraint stress induces bursting action potentials in LHb neurons, which are abolished by p11 knockdown. Overexpression of p11 in dopamine D2 receptor (D2R)-containing LHb neurons of control mice induces depression-like behaviors. These results have identified p11 in LHb as a key molecular determinant regulating negative emotions, which may help to understand the molecular and cellular basis of depression.

Purpose The current vitreous substitutes such as silicone oil, heavy silicone oil, and polymeric gels that are directly injected into vitreous cavity frequently cause severe intraocular complications. There is a very urgent need to find a more suitable artificial vitreous substitute for pars plana vitrectomy (PPV) surgery. Methods We have devised a novel capsular artificial vitreous using tailor-made silicone rubber elastomer. The novel device was implanted into the vitreous cavity of rabbit after PPV and the eye was examined by ophthalmoscopy, fundus photography, and tonometry during an 8-week treatment period. B-scan ultrasonography, electroretinogram (ERG), and histological studies by light microscopy were also performed at the end of 8 weeks.Results The novel artificial vitreous body consists of a thin vitreous-like capsule with a silicone tube-valve system. The capsule can be folded and implanted into vitreous cavity through 1.5 mm incision on sclera. Physiological balanced solution (PBS) was then injected into the capsule and inflated to support retina and control intraocular pressure (IOP) through the tube-valve system subsequently fixed under the conjunctiva. Experiments using rabbits showed that the novel vitreous body could effectively support the retina and apparently induced no significant pathological changes in the eye over 8 weeks. Conclusion This approach may provide a new research strategy in the vitreous replacement technology. The novel artificial vitreous body device can effectively support retina, control IOP, and has good biocompatibility. It may be a good alternative to injecting artificial vitreous although its tamponade properties and usefulness still have to be proven in complex vitreoretinal diseases.