Author Correction : Genetic effects on the timing of parturition and links to fetal birth weight

Publisher Copyright: © 2023 The Author(s).Correction to: Nature Genetics. Published online 3 April 2023. In the version of this article originally published, the surname of author Stefan Johansson was misspelled as Johanson. In the abstract and “Genome-wide association analyses” section of the Results, the number of loci associated with preterm birth was shown as six instead of seven. In addition, there was a production error in the Figure 1a y-axis units shown below 0, where “10” and “20” were shown as negative numbers. The errors have been corrected in the HTML and PDF versions of the article

Self- and informant-reported personality traits and vaccination against COVID-19

As COVID-19 vaccines’ accessibility has grown, so has the role of personal choice in vaccination, and not everybody is willing to vaccinate. Exploring personality traits’ associations with vaccination could highlight some person-level drivers of, and barriers to, vaccination. We used self- and informant-ratings of the Five-Factor Model domains and their subtraits (a) measured approximately at the time of vaccination with the 100 Nuances of Personality (100NP) item pool (N = 56,575) and (b) measured on average ten years before the pandemic with the NEO Personality Inventory-3 (NEO-PI-3; N = 3,168). We tested individual domains’ and either items’ (in the 100NP sample) or facets’ (in the NEO-PI-3 sample) associations with vaccination, as well as their collective ability to predict vaccination using elastic net models trained and tested in independent sample partitions. Although the NEO-PI-3 domains and facets did not predict vaccination ten years later, the domains correlated with vaccination in the 100NP sample, with vaccinated people scoring slightly higher on neuroticism and agreeableness and lower on openness, controlling for age, sex, and education. Collectively, the five domains predicted vaccination with an accuracy of r = .08. Associations were stronger at the item level. Vaccinated people were, on average, more science-minded, politically liberal, respectful of rules and authority, and anxious but less spiritual, religious, and self-assured. The 100NP items collectively predicted vaccination with r = .31 accuracy. We conclude that unvaccinated people may be a psychologically heterogeneous group and highlight some potential areas for action in vaccination campaigns

Uniting biobank resources reveals novel genetic pathways modulating susceptibility for atopic dermatitis

Publisher Copyright: © 2021 The AuthorsBackground: Atopic dermatitis (AD) is a common chronic inflammatory skin disease with high heritability. Previous genome-wide association studies have identified several loci predisposing to AD. These findings explain approximately 30% of the variance in AD susceptibility, suggesting that further work is required to fully understand the genetic underpinnings. Objective: We sought to gain additional understanding of the genetic contribution to AD risk by using biobank resources. Methods: We completed a genome-wide meta-analysis of AD in 796,661 individuals (Ncases = 22,474) from the FinnGen study, the Estonian Biobank, and the UK Biobank. We further performed downstream in silico analyses to characterize the risk variants at the novel loci. Results: We report 30 loci associating with AD (P < 5 × 10−8), 5 of which are novel. In 2 of the novel loci, we identified missense mutations with deleterious predictions in desmocollin 1 and serpin family B member 7, genes encoding proteins crucial to epidermal strength and integrity. Conclusions: These findings elucidate novel genetic pathways involved in AD pathophysiology. The likely involvement of desmocollin 1 and serpin family B member 7 in AD pathogenesis may offer opportunities for the development of novel treatment strategies for AD in the future.Peer reviewe

Uniting biobank resources reveals novel genetic pathways modulating susceptibility for atopic dermatitis

Publisher Copyright: © 2021 The AuthorsBackground: Atopic dermatitis (AD) is a common chronic inflammatory skin disease with high heritability. Previous genome-wide association studies have identified several loci predisposing to AD. These findings explain approximately 30% of the variance in AD susceptibility, suggesting that further work is required to fully understand the genetic underpinnings. Objective: We sought to gain additional understanding of the genetic contribution to AD risk by using biobank resources. Methods: We completed a genome-wide meta-analysis of AD in 796,661 individuals (Ncases = 22,474) from the FinnGen study, the Estonian Biobank, and the UK Biobank. We further performed downstream in silico analyses to characterize the risk variants at the novel loci. Results: We report 30 loci associating with AD (P < 5 × 10−8), 5 of which are novel. In 2 of the novel loci, we identified missense mutations with deleterious predictions in desmocollin 1 and serpin family B member 7, genes encoding proteins crucial to epidermal strength and integrity. Conclusions: These findings elucidate novel genetic pathways involved in AD pathophysiology. The likely involvement of desmocollin 1 and serpin family B member 7 in AD pathogenesis may offer opportunities for the development of novel treatment strategies for AD in the future.Peer reviewe

Global Biobank Meta-analysis Initiative : Powering genetic discovery across human disease

Funding Information: The work of the contributing biobanks was supported by numerous grants from governmental and charitable bodies. Biobank-specific acknowledgments and more detailed acknowledgments are included in Data S2. Initiative management, S.B.C. J.C. N.J.C. M.J.D. E.E.K. A.R.M. B.M.N. Y.O. A.V.P. D.A.v.H. R.G.W. C.J.W. W.Z. and S.Z.; individual biobank analysis, A.B. Y.B. B.M.B. C.D.B. S.C. T.-T.C. K.C. S.M.D. M.D. G.H.d.B. Y.D. N.J.D. M.-J.F. Y.-C.A.F. S.F. V.L.F. L.G.F. E.R.G. T.R.G. D.H.G. C.R.G. G.G.-A. S.E.G. L.A.G. C.H. J.B.H. W.E.H. H.H. K.H. N.I. A.I. R.J. M. Kurki, J.K. N.K. E.E.K. J.T.K. M. Kanai, T.L. K.L. M.H.L. S.L. K.L. Y.-F.L. V.L.F. R.J.F.L. E.A.L.-M. A.R.-M. S.M.-G. R.M. R.E.M. H.C.M. A.R.M. Y.M. H.M. S.E.M. I.Y.M. B.M. S.M. K.N. S.N. M.A.N.-A. K.N. Y.O. P.P. A.L.-P. A.P. B.P. S.P. M.H.P. D.J.R. N.R. M.D.R. A.R. C.S. S.S. S.S.S. J.A.S. P.S. I.S. T.T. R.T. K.T. J.U. D.A.v.H. B.V. M.V. Y.V. J.M.V. R.G.W. Y.W. S.J.W. B.N.W. K.-H.H.W. M.Z. X.Z. and S.Z.; individual biobank management, N.A. A.A.T. K.M.A.-D. P.A. K.C.B. M. Boehnke, M. Boezen, C.D.B. A.C. Z.C. C.-Y.C. J.C. N.J.C. S.M.D. S.F. Y.-C.A.F. S.F. E.F. T.G. C.R.G. C.J.G. Y.G. H.H. K.A.H. K.H. S.I.I. N.M.J. N.K. E.E.K. J.T.K. C.L. M.H.L. M.T.M.L. L.L. K.L. Y.-F.L. R.J.F.L. J.L. S.M. Y.M. K.M. I.Y.M. Y.O. C.M.O. A.V.P. B.P. D.J.P. D.J.R. M.D.R. S.S. J.W.S. H.S. K.S. T.T. U.T. R.C.T. D.A.v.H. M.V. R.G.W. D.C.W. C.W. J.W. M.Z. X.Z. and S.Z.; study design and interpretation of results, A.B. M. Boehnke, M. Boezen, B.M.B. T.-T.C. C.-Y.C. M.J.D. G.D.S. N.J.D. S.F. M.-J.F. H.K.F. E.R.G. A.G. T.G. J.B.H. J.H. K.H. R.J. M.K. E.E.K. T.K. C.M.L. V.L.F. E.A.L.-M. A.R.M. S.N. B.M.N. C.M.O. J.J.P. B.P. N.R. H.R. J.A.S. I.S. K.T. D.A.v.H. R.G.W. Y.W. D.C.W. S.J.W. C.J.W. B.N.W. J.W. K.-H.H.W. M.Z. H.Z. J.Z. W.Z. X.Z. and S.Z.; drafted and edited the paper, A.B. M. Boehnke, M. Boezen, M.J.D. G.H.d.B. N.J.D. T.R.G. J.B.H. N.I. N.M.J. M.K. V.L.F. S.M. A.R.M. H.M. S.N. B.M.N. C.M.O. B.P. H.R. C.S. J.A.S. J.W.S. K.T. Y.W. D.C.W. C.J.W. K.-H.H.W. H.Z. J.Z. W.Z. and S.Z.; primary meta-analysis and quality control, M.J.D. H.K.F. M. Kanai, J.K. J.T.K. M. Kurki, M.M. B.M.N. C.J.W. K.-H.H.W. and W.Z.; drug discovery: S.N. T.K. K.-H.H.W. W.Z. and Y.O.; fine mapping, M. Kanai, W.Z. M.J.D. and H.K.F.; polygenic risk score, Y.W. S.N. E.A.L.-M. S.K. K.T. K.L. M. Kanai, W.Z. K.W. M.-J.F. L.B. P.A. P.D. V.L.F. R.M. Y.M. B.B. S.S. J.U. E.R.G. N.J.C. I.S. Y.O. A.R.M. and J.B.H.; proteome-wide Mendelian randomization, H.Z. H.R. A.B. G.H. G.D.S. B.M.B. W.Z. B.M.N. T.R.G. and J.Z.; transcriptome-wide association study, A.B. J.B.H. W.Z. J.Z. M. Kanai, B.P. E.R.G. and N.J.C.; asthma, K.T. W.Z. Y.W. M. Kanai, S.N. Y.O. B.M.N. M.J.D. and A.R.M.; heart failure, K.-H.H.W. N.J.D. B.N.W. I.S. S.E.G. J.B.H. N.J.C. M.P. R.J.F.L. M.J.D. B.M.N. W.Z. W.E.H. and C.J.W.; idiopathic pulmonary fibrosis, J.J.P. W.Z. M.J.D. J.T.K. N.J.C. and J.B.H.; primary open-angle glaucoma, V.L.F. A.B. W.Z. Y.W. K.L. M. Kanai, E.A.L.-M. P.S. R.T. X.Z. S.N. S.S. Y.O. N.I. S.M. H.S. I.S. C.W. A.R.M. E.R.G. N.M.J. N.J.C. and J.B.H.; stroke, I.S. K.-H.H.W. W.H. B.N.W. W.Z. J.E.H. A.P. B.B. A.H.S. M.E.G. R.G.W. K.H. C.K. S.Z. M.J.D. B.M.N. and C.J.W.; venous thromboembolism, B.N.W. I.S. K.-H.H.W. B.B. V.L.F. K.T. M.D. B.N. W.Z. J.A.S. and C.J.W. All authors reviewed the manuscript. M.J.D. is a founder of Maze Therapeutics. B.M.N. is a member of the scientific advisory board at Deep Genomics and a consultant for Camp4 Therapeutics, Takeda Pharmaceutical, and Biogen. The spouse of C.J.W. works at Regeneron Pharmaceuticals. C.-Y.C. is employed by Biogen. C.R.G. owns stock in 23andMe, Inc. T.R.G. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. E.E.K. has received speaker fees from Regeneron, Illumina, and 23andMe and is a member of the advisory board for Galateo Bio. R.E.M. has received speaker fees from Illumina and is a scientific advisor to the Epigenetic Clock Development Foundation. G.D.S. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. K.S. and U.T. are employed by deCODE Genetics/Amgen, Inc. J.Z. has received research funding from various pharmaceutical companies to support the application of Mendelian randomization to drug target prioritization. S.M. is a co-founder of and holds stock in Seonix Bio. Publisher Copyright: © 2022Biobanks 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.Peer reviewe

Inframe insertion and splice site variants in MFGE8 associate with protection against coronary atherosclerosis

Publisher Copyright: © 2022. The Author(s).A genome-wide association study identifies MFGE8 as protective against coronary atherosclerosis in European and East Asian populations. Cardiovascular diseases are the leading cause of premature death and disability worldwide, with both genetic and environmental determinants. While genome-wide association studies have identified multiple genetic loci associated with cardiovascular diseases, exact genes driving these associations remain mostly uncovered. Due to Finland's population history, many deleterious and high-impact variants are enriched in the Finnish population giving a possibility to find genetic associations for protein-truncating variants that likely tie the association to a gene and that would not be detected elsewhere. In a large Finnish biobank study FinnGen, we identified an association between an inframe insertion rs534125149 in MFGE8 (encoding lactadherin) and protection against coronary atherosclerosis. This variant is highly enriched in Finland, and the protective association was replicated in meta-analysis of BioBank Japan and Estonian biobank. Additionally, we identified a protective association between splice acceptor variant rs201988637 in MFGE8 and coronary atherosclerosis, independent of the rs534125149, with no significant risk-increasing associations. This variant was also associated with lower pulse pressure, pointing towards a function of MFGE8 in arterial aging also in humans in addition to previous evidence in mice. In conclusion, our results suggest that inhibiting the production of lactadherin could lower the risk for coronary heart disease substantially.Peer reviewe

Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease.

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases

Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-alpha in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization. Here the authors identify genetic effectors of the level of inflammation-related plasma proteins and use Mendelian randomization to identify proteins that contribute to immune-mediated disease risk

Genetic effects on the timing of parturition and links to fetal birth weight.

This is the final version. Available from Nature Research via the DOI in this record. Data availability: Cohorts should be contacted individually for access to raw genotype and phenotype data, as each cohort has different data access policies. Summary statistics from the meta-analysis, excluding 23andMe, are available at the EGG website (https://egg-consortium.org/), and access to the weights for constructing the polygenic score of gestational duration excluding 23andMe are available at the PGS Catalog (https://www.pgscatalog.org/, score ID: PGS002806). Access to the full set, including 23andMe results, can be obtained after approval from 23andMe is presented to the corresponding author or by completion of a Data Transfer Agreement (https://research.23andme.com/dataset-access/), which exists to protect the privacy of 23andMe participants. Access to the Danish National Birth Cohort (phs000103.v1.p1), Hyperglycemia and Adverse Pregnancy Outcome (phs000096.v4.p1) and Genomic and Proteomic Network (phs000714.v1.p1) individual-level phenotype and genetic data can be obtained through dbGaP Authorized Access portal (https://dbgap.ncbi.nlm.nih.gov/dbgap/aa/wga.cgi?page=login). The informed consent under which the data or samples were collected is the basis for determining the appropriateness of sharing data through unrestricted-access databases or NIH-designated controlled-access data repositories. The summary statistics used in this publication other than the one generated are available at the following links: fetal GWAS of gestational duration (http://egg-consortium.org/gestational-duration-2019.html), fetal and maternal GWAS of birth weight (http://egg-consortium.org/birth-weight-2019.html), miscarriage (http://www.geenivaramu.ee/tools/misc_sumstats.zip), age at first birth, estradiol (women), endometriosis, number of live births and age at menarche (http://www.nealelab.is), age at menopause (https://www.reprogen.org), testosterone (women)58, SHBG, testosterone and CBAT (https://doi.org/10.6084/m9.figshare.c.5304500.v1), pelvic organ prolapse and leiomyoma of the uterus (https://www.finngen.fi/fi), polycystic ovary syndrome (https://www.repository.cam.ac.uk/handle/1810/283491 and https://www.finngen.fi/fi) and pre-eclampsia (European Genome-phenome Archive, https://ega-archive.org, EGAD00010001984). Pan-UK Biobank data are available at https://pan.ukbb.broadinstitute.org/. Precomputed LD scores for European populations (https://data.broadinstitute.org/alkesgroup/LDSCORE/eur_w_ld_chr.tar.bz2) and multi-tissue gene expression precomputed stratified LD scores (https://alkesgroup.broadinstitute.org/LDSCORE/LDSC_SEG_ldscores/Multi_tissue_gene_expr_1000Gv3_ldscores.tgz) are available. eQTL data from GTEx are available at https://gtexportal.org/home/ and from endometrium at http://reproductivegenomics.com.au/shiny/endo_eqtl_rna/. Protein QTL data were obtained from https://www.omicscience.org/apps/pgwas/. Genome Reference Consortium Human Build 37 (hg19) available at https://www.ncbi.nlm.nih.gov/data-hub/genome/GCF_000001405.13/.Code availability: Code for this project has been structured using a Snakemake workflow65 and is available at https://github.com/PerinatalLab/metaGWAS. A public release of it has been deposited in Zenodo (https://doi.org/10.5281/zenodo.7311977).The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.Swedish Research CouncilSwedish Research CouncilResearch Council of NorwayResearch Council of NorwayMarch of Dimesunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of HealthNorwegian Diabetes AssociationNils Normans minnegaveNorwegian Research CouncilMedical Research CouncilBritish Heart FoundationResearch Council of NorwayBritish Heart FoundationDaniel B. Burke Chair for Diabetes Research and NIHCHOPEuropean Regional Development Fund and the programme Mobilitas PlussWellcome Trust and Royal Society Sir Henry Dale FellowshipWellcome TrustOak FoundationFonds de la recherche du Québec en santéUS National Institutes of HealthNovo Nordisk FoundationNovo Nordisk FoundationNovo Nordisk Foundatio

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities