| 1. |
- Mullins, Niamh, et al.
(author)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Journal article (peer-reviewed)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 2. |
- Docherty, Anna R, et al.
(author)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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In: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Journal article (peer-reviewed)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 3. |
- Zhou, Wei, et al.
(author)
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Global Biobank Meta-analysis Initiative : Powering genetic discovery across human disease
- 2022
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In: Cell Genomics. - : Elsevier. - 2666-979X. ; 2:10
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Journal article (peer-reviewed)abstract
- Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.
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| 4. |
- Guintivano, Jerry, et al.
(author)
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Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression
- 2023
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In: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 180:12, s. 884-895
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD.METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system.RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD.CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).
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| 5. |
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| 6. |
- Bai, Xuemei, et al.
(author)
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Translating Earth system boundaries for cities and businesses
- 2024
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In: Nature Sustainability. - 2398-9629. ; 7, s. 108-119
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Research review (peer-reviewed)abstract
- Operating within safe and just Earth system boundaries requires mobilizing key actors across scale to set targets and take actions accordingly. Robust, transparent and fair cross-scale translation methods are essential to help navigate through the multiple steps of scientific and normative judgements in translation, with clear awareness of associated assumptions, bias and uncertainties. Here, through literature review and expert elicitation, we identify commonly used sharing approaches, illustrate ten principles of translation and present a protocol involving key building blocks and control steps in translation. We pay particular attention to businesses and cities, two understudied but critical actors to bring on board.
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| 7. |
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| 8. |
- Moreno, C. Isabel, et al.
(author)
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Tropical tropospheric aerosol sources and chemical composition observed at high altitude in the Bolivian Andes
- 2024
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In: Atmospheric Chemistry And Physics. - 1680-7316 .- 1680-7324. ; 24:5, s. 2837-2860
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Journal article (peer-reviewed)abstract
- The chemical composition of PM10 and non-overlapping PM2.5 was studied at the summit of Mt. Chacaltaya (5380 m a.s.l., lat. −16.346950°, long. −68.128250°) providing a unique long-term record spanning from December 2011 to March 2020. The chemical composition of aerosol at the Chacaltaya Global Atmosphere Watch (GAW) site is representative of the regional background, seasonally affected by biomass burning practices and by nearby anthropogenic emissions from the metropolitan area of La Paz–El Alto. Concentration levels are clearly influenced by seasons with minima occurring during the wet season (December to March) and maxima occurring during the dry and transition seasons (April to November). Ions, total carbon (EC + OC), and saccharide interquartile ranges for concentrations are 558–1785, 384–1120, and 4.3–25.5 ng m−3 for bulk PM10 and 917–2308, 519–1175, and 3.9–24.1 ng m−3 for PM2.5, respectively, with most of the aerosol seemingly present in the PM2.5 fraction. Such concentrations are overall lower compared to other high-altitude stations around the globe but higher than Amazonian remote sites (except for OC). For PM10, there is dominance of insoluble mineral matter (33 %–56 % of the mass), organic matter (7 %–34 %), and secondary inorganic aerosol (15 %–26 %). Chemical composition profiles were identified for different origins: glucose, and for the nearby urban and rural areas; OC, EC, , K+, acetate, formate, levoglucosan, and some F− and Br− for biomass burning; for aged marine emissions from the Pacific Ocean; arabitol, mannitol, and glucose for biogenic emissions; for soil dust; and and some Cl− for volcanism. Regional biomass burning practices influence the soluble fraction of the aerosol between June and November. The organic fraction is present all year round and has both anthropogenic (biomass burning and other combustion sources) and natural (primary and secondary biogenic emissions) origins, with the OC/EC mass ratio being practically constant all year round (10.5 ± 5.7, IQR 8.1–13.3). Peruvian volcanism has dominated the concentration since 2014, though it presents strong temporal variability due to the intermittence of the sources and seasonal changes in the transport patterns. These measurements represent some of the first long-term observations of aerosol chemical composition at a continental high-altitude site in the tropical Southern Hemisphere.
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| 9. |
- Namba, Shinichi, et al.
(author)
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Common germline risk variants impact somatic alterations and clinical features across cancers
- 2023
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In: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 83:1, s. 20-27
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Journal article (peer-reviewed)abstract
- Aggregation of genome-wide common risk variants, such as polygenic risk score (PRS), can measure genetic susceptibility to cancer. A better understanding of how common germline variants associate with somatic alterations and clinical features could facilitate personalized cancer prevention and early detection. We constructed PRSs from 14 genome-wide association studies (median n = 64,905) for 12 cancer types by multiple methods and calibrated them using the UK Biobank resources (n = 335,048). Meta-analyses across cancer types in The Cancer Genome Atlas (n = 7,965) revealed that higher PRS values were associated with earlier cancer onset and lower burden of somatic alterations, including total mutations, chromosome/arm somatic copy-number alterations (SCNA), and focal SCNAs. This contrasts with rare germline pathogenic variants (e.g., BRCA1/2 variants), showing heterogeneous associations with somatic alterations. Our results suggest that common germline cancer risk variants allow early tumor development before the accumulation of many somatic alterations characteristic of later stages of carcinogenesis.SIGNIFICANCE: Meta-analyses across cancers show that common germline risk variants affect not only cancer predisposition but the age of cancer onset and burden of somatic alterations, including total mutations and copy-number alterations.
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| 10. |
- Watson, Hunna J., et al.
(author)
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Common Genetic Variation and Age of Onset of Anorexia Nervosa
- 2022
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In: BIOLOGICAL PSYCHIATRY: GLOBAL OPEN SCIENCE. - : Elsevier BV. - 2667-1743. ; 2:4, s. 368-378
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Journal article (peer-reviewed)abstract
- BACKGROUND: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.METHODS: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (,13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.RESULTS: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early-and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early -onset AN.CONCLUSIONS: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
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