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

Genetic legacy of ancient hunter-gatherer Jomon in Japanese populations

Yamamoto K., Namba S., Sonehara K., et al. Genetic legacy of ancient hunter-gatherer Jomon in Japanese populations. Nature Communications 15, 9780 (2024); https://doi.org/10.1038/s41467-024-54052-0.The tripartite ancestral structure is a recently proposed model for the genetic origin of modern Japanese, comprising indigenous Jomon hunter-gatherers and two additional continental ancestors from Northeast Asia and East Asia. To investigate the impact of the tripartite structure on genetic and phenotypic variation today, we conducted biobank-scale analyses by merging Biobank Japan (BBJ; n = 171,287) with ancient Japanese and Eurasian genomes (n = 22). We demonstrate the applicability of the tripartite model to Japanese populations throughout the archipelago, with an extremely strong correlation between Jomon ancestry and genomic variation among individuals. We also find that the genetic legacy of Jomon ancestry underlies an elevated body mass index (BMI). Genome-wide association analysis with rigorous adjustments for geographical and ancestral substructures identifies 132 variants that are informative for predicting individual Jomon ancestry. This prediction model is validated using independent Japanese cohorts (Nagahama cohort, n = 2993; the second cohort of BBJ, n = 72,695). We further confirm the phenotypic association between Jomon ancestry and BMI using East Asian individuals from UK Biobank (n = 2286). Our extensive analysis of ancient and modern genomes, involving over 250,000 participants, provides valuable insights into the genetic legacy of ancient hunter-gatherers in contemporary populations

Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease

Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies

In a genome-wide association study (GWAS) meta-analysis of 688,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries across diverse and admixed ancestries, we identify 697 associations at 635 loci, 293 of which are novel. Using fine-mapping and functional tools, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. A neural cell-type enrichment analysis utilizing single-cell data implicates excitatory, inhibitory, and medium spiny neurons and the involvement of amygdala neurons in both mouse and human single-cell analyses. The associations are enriched for antidepressant targets and provide potential repurposing opportunities. Polygenic scores trained using European or multi-ancestry data predicted MD status across all ancestries, explaining up to 5.8% of MD liability variance in Europeans. These findings advance our global understanding of MD and reveal biological targets that may be used to target and develop pharmacotherapies addressing the unmet need for effective treatment

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors (vol 52, pg 1303, 2020): Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors (Nature Genetics, (2020), 52, 12, (1303-1313), 10.1038/s41588-020-00725-7)

In the version of this article initially published, the following statement was missing from the Acknowledgements: “We are grateful to the GenoBiRD core facility (Biogenouest), the Clinical Investigation Center (INSERM CIC1413) and the Center of Biological Resources in Nantes (BB-0033-00040; CHU Nantes, France) for their assistance in managing and genotyping the ICAN and PREGO biobanks. R.R. was supported by the French Regional Council of Pays-de-la-Loire (VaCaRMe program) and the Agence Nationale de la Recherche (ANR-15-CE17-0008-01 to G.L). H.D. and R.B. were supported by the French Ministry of Health (clinical trial NCT02848495 to H.D.), the Genavie Foundation, the Société Française de Radiologie and the Société Française de Neuroradiologie.” The error has been corrected in the HTML and PDF versions of the article. *Lists of authors and their affiliations appear online

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits

Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease. © The Author(s) 2024. corrected publication 2024

Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.Peer reviewe