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The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
Three new species of Paragnorimus Becker are described: Paragnorimus atratus n. sp. from Guatemala, P. hondurensis n. sp. from Honduras and Nicaragua, and P. howdeni n. sp. from Guatemala. Based on the overlapping characters of these new species, the genus Peltotrichius Howden is placed in synonymy with Paragnorimus. Paragnorimus is given a broader definition to encompass the new species and the two species formerly placed in the genus Peltotrichius.
Classificatory changes are made for some taxa of New World Melolonthinae based on the examination of specimens (including type specimens) and a reevaluation of some of the characters used to justify previous classification decisions. Blepharotoma angustata (Blanchard) (new combination) is transferred from the genus Aplodema Blanchard. The Neotropical members of the genus Heteronyx Guérin-Méneville are transferred to the genus Blepharotoma resulting in the following new combinations: Blepharotoma boliviana (Moser), Blepharotoma corumbana (Moser), Blepharotoma cuyabana (Moser), Blepharotoma heynei (Moser), and Blepharotoma schencklingi (Moser). The genus Blepharotoma is transferred from the tribe Liparetrini to the tribe Sericoidini. The genus Aplodema and the junior synonym Haplodema Harold are transferred from the tribe Liparetrini to the tribe Sericoidini and synonymized with the genus Sericoides Guérin-Méneville. Sericoides magellanica (Blanchard) (new combination) is transferred from the genus Aplodema and placed as a senior synonym of Apterodema acuticollis Fairmaire (new synonymy). Ampliodactylus (new genus) is described for two southern South American species: Ampliodactylus marmoratus (Curtis) (new combination) and Ampliodactylus vestitus (Philippi) (new combination). The genus Chremastodus Solier is placed in synonymy with the genus Macrodactylus Dejean (Macrodactylini) and Chremastodus pubescens Solier is placed as a junior synonym of Macrodactylus chilensis Solier (new synonymy). Macrodactylus crassipes Philippi and Macrodactylus nigrinus Philippi are placed as junior synonyms of Macrodactylus farinosus Philippi (new synonymies). The genus Astaenosiagum Martínez is placed in synonymy with the genus Pristerophora Harold (Macrodactylini). Pristerophora longipes (Philippi) (new combination) is transferred from the genus Astaenosiagum and Schizochelus ursulus Philippi is placed as a junior synonym of this species (new synonymy). Pristerophora paulseni (new species) is described. Pristerophora picipennis (Solier) is placed as a senior synonym of Schizochelus breviventris Philippi (new synonymy) and Schizochelus serratus Philippi (new synonymy). Pusiodactylus (new genus) is described for two southern South American species: Pusiodactylus mondacai (new species) and Pusiodactylus flavipennis (Philippi) (new combination). The genus Paulosawaya Martínez and D'Andretta is placed in synonymy with the genus Clavipalpus Laporte (Macrodactylini) resulting in the new combination Clavipalpus ornatissima (Martínez and D'Andretta). The following replacement names are proposed for three junior secondary homonyms the genus Plectris LePeletier and Serville: Plectris evansi (new name) for Plectris cinerascens Moser (junior secondary homonym of Plectris cinerascens (Blanchard)), Plectris katovichi (new name) for Plectris bonariensis Frey (junior secondary homonym of Plectris bonariensis (Bruch)), and Plectris tacoma (new name) for Plectris comata (Blanchard) (junior secondary homonym of Plectris comata (Blanchard)).
The name Melolontha hypocrita Mannerheim, 1829 has been long unused, even though it is the type species of Hyporhiza Dejean, 1833. I examined the only known specimen from the type series and here designate it as the lectotype. Examination of this lectotype reveals that this species is best placed in the genus Rhinaspis Perty, 1830. Consequently, the genus Hyporhiza Dejean, 1833 is confi rmed as a junior synonym of Rhinaspis. Further, the replacement name Rhinaspis fuhrmanni is proposed for Rhinaspis hypocrita (Blanchard, 1850), a new secondary homonym of Rhinaspis hypocrita (Mannerheim, 1829). A homonymy problem was also discovered and corrected for the genus Plectris LePeletier and Serville, 1828. The replacement name Plectris schoolmeestersi is proposed for Plectris paraguayensis Moser, 1924, which is a secondary junior homonym of Plectris paraguayensis (Moser, 1921).