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During the peak of hospitalizations of patients with severe Covid-19 in Italy and Spain in March, a group of researchers in these and other countries obtained and analyzed samples, resulting in the identification of two chromosomal loci associated with the disorder.

Alison Klein and colleagues report a genome-wide meta-analysis to identify loci associated with pancreatic cancer risk. They identify associated variants at 17q25.1, 3q29, 7p13 and 2p13.3. Pancreatic cancer is the fourth leading cause of cancer death in the developed world 1 . Both inherited high-penetrance mutations in BRCA2 (ref. 2 ), ATM 3 , PALB2 (ref. 4 ), BRCA1 (ref. 5 ), STK11 (ref. 6 ), CDKN2A 7 and mismatch-repair genes 8 and low-penetrance loci are associated with increased risk 9 , 10 , 11 , 12 . To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 ( LINC00673 , rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19–1.34, P = 1.42 × 10 −14 ), 7p13 ( SUGCT , rs17688601, OR = 0.88, 95% CI = 0.84–0.92, P = 1.41 × 10 −8 ) and 3q29 ( TP63 , rs9854771, OR = 0.89, 95% CI = 0.85–0.93, P = 2.35 × 10 −8 ). We detected significant association at 2p13.3 ( ETAA1 , rs1486134, OR = 1.14, 95% CI = 1.09–1.19, P = 3.36 × 10 −9 ), a region with previous suggestive evidence in Han Chinese 12 . We replicated previously reported associations at 9q34.2 ( ABO ) 9 , 13q22.1 ( KLF5 ) 10 , 5p15.33 ( TERT and CLPTM1 ) 10 , 11 , 13q12.2 ( PDX1 ) 11 , 1q32.1 ( NR5A2 ) 10 , 7q32.3 ( LINC-PINT ) 11 , 16q23.1 ( BCAR1 ) 11 and 22q12.1 ( ZNRF3 ) 11 . Our study identifies new loci associated with pancreatic cancer risk.

A recent genetic association study 1 identified a gene cluster on chromosome 3 as a risk locus for respiratory failure after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A separate study (COVID-19 Host Genetics Initiative) 2 comprising 3,199 hospitalized patients with coronavirus disease 2019 (COVID-19) and control individuals showed that this cluster is the major genetic risk factor for severe symptoms after SARS-CoV-2 infection and hospitalization. Here we show that the risk is conferred by a genomic segment of around 50 kilobases in size that is inherited from Neanderthals and is carried by around 50% of people in south Asia and around 16% of people in Europe. Risk of severe COVID-19 is conferred by a genomic segment that is inherited from Neanderthals and is carried by around 50% and 16% of people in south Asia and Europe, respectively.

Aneuploidy is a hallmark of cancer and underlies genetic disorders characterized by severe developmental defects, yet the molecular mechanisms explaining its effects on cellular physiology remain elusive. Here we show, using a series of human cells with defined aneuploid karyotypes, that gain of a single chromosome increases genomic instability. Next-generation sequencing and SNP-array analysis reveal accumulation of chromosomal rearrangements in aneuploids, with break point junction patterns suggestive of replication defects. Trisomic and tetrasomic cells also show increased DNA damage and sensitivity to replication stress. Strikingly, we find that aneuploidy-induced genomic instability can be explained by the reduced expression of the replicative helicase MCM2-7. Accordingly, restoring near-wild-type levels of chromatin-bound MCM helicase partly rescues the genomic instability phenotypes. Thus, gain of chromosomes triggers replication stress, thereby promoting genomic instability and possibly contributing to tumorigenesis. One of the hallmarks of cancer cells is aneuploidy, however the molecular effects are poorly understood. Here the authors show that trisomic and tetrasomic cells display increased genomic instability and reduced levels of the helicase MCM2-7.

There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01–0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m 2 ). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m 2 for each Mb of total deletion burden ( P  = 2.5 × 10 −10 , 6.0 × 10 −5 , and 2.9 × 10 −3 ). Our study provides evidence that the same genes (e.g., MC4R , FIBIN , and FMO5 ) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders. Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.

Tin Aung, Christopher Hammond and colleagues report the results of a large genome-wide association study of intraocular pressure. They identify four new loci associated with this trait and show that three of these loci are associated with risk of primary open-angle glaucoma. Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene ( P = 4.19 × 10 −8 for rs6445055), two on chromosome 9 ( P = 2.80 × 10 −11 for rs2472493 near ABCA1 and P = 6.39 × 10 −11 for rs8176693 within ABO ) and one on chromosome 11p11.2 (best P = 1.04 × 10 −11 for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

The genetics of human height A genome-wide association (GWA) study of more than 180,000 individuals has identified hundreds of genetic variants in at least 180 loci associated with adult human height. The loci are not clustered randomly but are enriched for genes involved in growth-related processes that influence adult height. This demonstrates that GWA studies of common human traits, and therefore of many diseases, can identify large numbers of loci that implicate potential causal genes. This very large genome-wide association study identifies hundreds of new genetic variants influencing adult height in at least 180 loci enriched for genes involved in skeletal growth defects. The results show that the likely causal gene is often located near the most strongly associated variant, that many loci have multiple independently associated variants and that associated variants are enriched for likely functional effects on genes. Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits 1 , but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait 2 , 3 . The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways ( P = 0.016) and that underlie skeletal growth defects ( P  < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.

Ian Tomlinson, Richard Houlston, Malcolm Dunlop and colleagues report results of a large genome-wide association study of colorectal cancer. They identify four new risk loci and suggest that many more loci of similar effect size are likely to exist. Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10 −10 and rs6687758, OR = 1.09, P = 2.27 × 10 −9 ), 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10 −8 ), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10 −10 and rs7136702, OR = 1.06, P = 4.02 × 10 −8 ) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10 −10 ). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.

Toshimasa Yamauchi and colleagues report results of a genome-wide association study of type 2 diabetes in the Japanese population. They identify new risk loci at UBE2E2 and C2CD4A-C2CD4B and show that the latter is also associated with type 2 diabetes risk in Europeans. We conducted a genome-wide association study of type 2 diabetes (T2D) using 459,359 SNPs in a Japanese population with a three-stage study design (stage 1, 4,470 cases and 3,071 controls; stage 2, 2,886 cases and 3,087 controls; stage 3, 3,622 cases and 2,356 controls). We identified new associations in UBE2E2 on chromosome 3 and in C2CD4A-C2CD4B on chromosome 15 at genome-wide significant levels (rs7612463 in UBE2E2 , combined P = 2.27 × 10 −9 ; rs7172432 in C2CD4A-C2CD4B , combined P = 3.66 × 10 −9 ). The association of these two loci with T2D was replicated in other east Asian populations. In the European populations, the C2CD4A-C2CD4B locus was significantly associated with T2D, and a combined analysis of all populations gave P = 8.78 × 10 −14 , whereas the UBE2E2 locus did not show association to T2D. In conclusion, we identified two new loci at UBE2E2 and C2CD4A-C2CD4B associated with susceptibility to T2D.