Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations

Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes1. This recent study—and most other large-scale human genetics studies—was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10−6). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) R01MH109536 R01MH118278 R01MH124839 U01MH109536UK Research & Innovation (UKRI) Medical Research Council UK (MRC)Janette Mary O'Neil Research FellowshipNational Health and Medical Research Council (NHMRC) of AustraliaInstituto de Salud Carlos III Spanish GovernmentEuropean Regional Development Fund/European Social Fund A Way to Make Europe/Investing in Your FutureInstituto de Salud Carlos III Spanish GovernmentEuropean Regional Development Fund Funds from the European Commission, A Way of Making EuropeCentro de Investigacion Biomedica en Red de Salud Mental, Madrid Regional GovernmentFundacion Familia Alonso MR/L010305/1 MR/P005748/1Fundacion Alicia Koplowitz 1R01MH124851European Regional Development Fund Funds from the European Commission R01MH100125 1I01CX000995Ministry of Health, Italy P50MH066392Takeda Pharmaceutical Company LtdHoffmann-La RocheHoffmann-La RocheUnited States Department of Health & Human Services National Institutes of Health (NIH) - USA 1037196 1176716United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) 513861Australian Schizophrenia Research Bank PI18/00238 PI18/00467 B2017/BMD-3740 AGES-CM-2 115916 777394Neuroscience Research Australia PI18/00213 CPII21/00008 MS16/00153 PI19/024 R01MH085542 R01MH093725 P50MH080405 R01MH097276 RO1MH-075916 P50M096891 P50MH084053S1 R37MH057881 AG02219 AG05138 MH06692 R01MH110921 R01MH109677 R01MH109897 U01MH103392 U01MH116442 ZIC MH002903 HHSN271201300031C R01AG067025 R01AG065582 R01AG050986 R01MH125246 R01MH10605

Electrical switching of ferro-rotational order in nano-thick 1T-TaS2_2 crystals

Hysteretic switching of domain states is a salient character of all ferroic materials and the foundation for their multifunctional applications. Ferro-rotational order is emerging as a new type of ferroic order featuring structural rotations, but its controlled switching remains elusive due to its invariance under both time reversal and spatial inversion. Here, we demonstrate electrical switching of ferro-rotational domain states in nanometer-thick 1T-TaS$_2$ crystals in its charge-density-wave phases. Cooling from the high-symmetry phase to the ferro-rotational phase under an external electric field induces domain state switching and domain wall formation, realized in a simple two-terminal configuration using a volt-scale voltage. Although the electric field does not couple with the order due to symmetry mismatch, it drives domain wall propagation to give rise to reversible, durable, and nonvolatile isothermal state switching at room temperature. These results pave the path for manipulation of the ferro-rotational order and its nanoelectronic applications

Impacts of Duck-Origin Parvovirus Infection on Cherry Valley Ducklings From the Perspective of Gut Microbiota

Duck-origin goose parvovirus (D-GPV) is the causative agent of beak atrophy and dwarfism syndrome (BADS), characterized by growth retardation, skeletal dysplasia, and persistent diarrhea. However, the pathogenic mechanism of D-GPV remains undefined. Here, we first reported the gut microbiome diversity of D-GPV infected Cherry Valley ducks. In the investigation for the influence of D-GPV infection on gut microbiota through a period of infection, we found that D-GPV infection caused gut microbiota dysbiosis by reducing the prevalence of the dominant genera and decreasing microbial diversity. Furthermore, exfoliation of the intestinal epithelium, proliferation of lymphocytes, up-regulated mRNA expression of pro-inflammatory TNF-α, IL-1β, IL-6, IL-17A, and IL-22 and down-regulated mRNA expression of anti-inflammatory IL-10 and IL-4 occurred when D-GPV targeted in cecal epithelium. In addition, the content of short chain fatty acids (SCFAs) in cecal contents was significantly reduced after D-GPV infection. Importantly, the disorder of pro-inflammatory and anti-inflammatory cytokines was associated with the decrease of SCFAs-producing bacteria and the enrichment of opportunistic pathogens. Collectively, the decrease of SCFAs and the enrichment of pathogen-containing gut communities promoted intestinal inflammatory injury. These results may provide a new insight that target the gut microbiota to understand the progression of BADS disease and to research the pathogenic mechanism of D-GPV

SNPs associated with testosterone levels influence human facial morphology

Many factors influence human facial morphology, including genetics, age, nutrition, biomechanical forces, and endocrine factors. Moreover, facial features clearly differ between males and females, and these differences are driven primarily by the influence of sex hormones during growth and development. Specific genetic variants are known to influence circulating sex hormone levels in humans, which we hypothesize, in turn, affect facial features. In this study, we investigated the effects of testosterone-related genetic variants on facial morphology. We tested 32 genetic variants across 22 candidate genes related to levels of testosterone, sex hormone-binding globulin (SHGB) and dehydroepiandrosterone sulfate (DHEAS) in three cohorts of healthy individuals for which 3D facial surface images were available (Pittsburgh 3DFN, Penn State and ALSPAC cohorts; total n = 7418). Facial shape was described using a recently developed extension of the dense-surface correspondence approach, in which the 3D facial surface was partitioned into a set of 63 hierarchically organized modules. Each variant was tested against each of the facial surface modules in a multivariate genetic association-testing framework and meta-analyzed. Additionally, the association between these candidate SNPs and five facial ratios was investigated in the Pittsburgh 3DFN cohort. Two significant associations involving intronic variants of SHBG were found: both rs12150660 (p = 1.07E-07) and rs1799941 (p = 6.15E-06) showed an effect on mandible shape. Rs8023580 (an intronic variant of NR2F2-AS1) showed an association with the total and upper facial width to height ratios (p = 9.61E-04 and p = 7.35E-04, respectively). These results indicate that testosterone-related genetic variants affect normal-range facial morphology, and in particular, facial features known to exhibit strong sexual dimorphism in humans

3D facial phenotyping by biometric sibling matching used in contemporary genomic methodologies

The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height). Here we report on a data-driven, family-informed strategy to facial phenotyping that searches for biologically relevant traits and reduces multivariate 3D facial shape variability into amendable univariate measurements, while preserving its structurally complex nature. We performed a biometric identification of siblings in a sample of 424 children, defining 1,048 sib-shared facial traits. Subsequent quantification and analyses in an independent European cohort (n = 8,246) demonstrated significant heritability for a subset of traits (0.17–0.53) and highlighted 218 genome-wide significant loci (38 also study-wide) associated with facial variation shared by siblings. These loci showed preferential enrichment for active chromatin marks in cranial neural crest cells and embryonic craniofacial tissues and several regions harbor putative craniofacial genes, thereby enhancing our knowledge on the genetic architecture of normal-range facial variation

Genome scans of facial features in East Africans and cross-population comparisons reveal novel associations

Facial morphology is highly variable, both within and among human populations, and a sizable portion of this variation is attributable to genetics. Previous genome scans have revealed more than 100 genetic loci associated with different aspects of normal-range facial variation. Most of these loci have been detected in Europeans, with few studies focusing on other ancestral groups. Consequently, the degree to which facial traits share a common genetic basis across diverse sets of humans remains largely unknown. We therefore investigated the genetic basis of facial morphology in an East African cohort. We applied an open-ended data-driven phenotyping approach to a sample of 2,595 3D facial images collected on Tanzanian children. This approach segments the face into hierarchically arranged, multivariate features that capture the shape variation after adjusting for age, sex, height, weight, facial size and population stratification. Genome scans of these multivariate shape phenotypes revealed significant (p < 2.5 × 10−8) signals at 20 loci, which were enriched for active chromatin elements in human cranial neural crest cells and embryonic craniofacial tissue, consistent with an early developmental origin of the facial variation. Two of these associations were in highly conserved regions showing craniofacial-specific enhancer activity during embryological development (5q31.1 and 12q21.31). Six of the 20 loci surpassed a stricter threshold accounting for multiple phenotypes with study-wide significance (p < 6.25 × 10−10). Cross-population comparisons indicated 10 association signals were shared with Europeans (seven sharing the same associated SNP), and facilitated fine-mapping of causal variants at previously reported loci. Taken together, these results may point to both shared and population-specific components to the genetic architecture of facial variation