Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Kentistou KA

PROVIDER: S-EPMC11250262 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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

Kentistou Katherine A KA Kaisinger Lena R LR Stankovic Stasa S Vaudel Marc M Mendes de Oliveira Edson E Messina Andrea A Walters Robin G RG Liu Xiaoxi X Busch Alexander S AS Helgason Hannes H Thompson Deborah J DJ Santoni Federico F Petricek Konstantin M KM Zouaghi Yassine Y Huang-Doran Isabel I Gudbjartsson Daniel F DF Bratland Eirik E Lin Kuang K Gardner Eugene J EJ Zhao Yajie Y Jia Raina Y RY Terao Chikashi C Riggan Marjorie J MJ Bolla Manjeet K MK Yazdanpanah Mojgan M Yazdanpanah Nahid N Bradfield Jonathan P JP Broer Linda L Campbell Archie A Chasman Daniel I DI Cousminer Diana L DL Franceschini Nora N Franke Lude H LH Girotto Giorgia G He Chunyan C Järvelin Marjo-Riitta MR Joshi Peter K PK Kamatani Yoichiro Y Karlsson Robert R Luan Jian'an J Lunetta Kathryn L KL Mägi Reedik R Mangino Massimo M Medland Sarah E SE Meisinger Christa C Noordam Raymond R Nutile Teresa T Concas Maria Pina MP Polašek Ozren O Porcu Eleonora E Ring Susan M SM Sala Cinzia C Smith Albert V AV Tanaka Toshiko T van der Most Peter J PJ Vitart Veronique V Wang Carol A CA Willemsen Gonneke G Zygmunt Marek M Ahearn Thomas U TU Andrulis Irene L IL Anton-Culver Hoda H Antoniou Antonis C AC Auer Paul L PL Barnes Catriona L K CLK Beckmann Matthias W MW Berrington de Gonzalez Amy A Bogdanova Natalia V NV Bojesen Stig E SE Brenner Hermann H Buring Julie E JE Canzian Federico F Chang-Claude Jenny J Couch Fergus J FJ Cox Angela A Crisponi Laura L Czene Kamila K Daly Mary B MB Demerath Ellen W EW Dennis Joe J Devilee Peter P De Vivo Immaculata I Dörk Thilo T Dunning Alison M AM Dwek Miriam M Eriksson Johan G JG Fasching Peter A PA Fernandez-Rhodes Lindsay L Ferreli Liana L Fletcher Olivia O Gago-Dominguez Manuela M García-Closas Montserrat M García-Sáenz José A JA González-Neira Anna A Grallert Harald H Guénel Pascal P Haiman Christopher A CA Hall Per P Hamann Ute U Hakonarson Hakon H Hart Roger J RJ Hickey Martha M Hooning Maartje J MJ Hoppe Reiner R Hopper John L JL Hottenga Jouke-Jan JJ Hu Frank B FB Huebner Hanna H Hunter David J DJ Jernström Helena H John Esther M EM Karasik David D Khusnutdinova Elza K EK Kristensen Vessela N VN Lacey James V JV Lambrechts Diether D Launer Lenore J LJ Lind Penelope A PA Lindblom Annika A Magnusson Patrik K E PKE Mannermaa Arto A McCarthy Mark I MI Meitinger Thomas T Menni Cristina C Michailidou Kyriaki K Millwood Iona Y IY Milne Roger L RL Montgomery Grant W GW Nevanlinna Heli H Nolte Ilja M IM Nyholt Dale R DR Obi Nadia N O'Brien Katie M KM Offit Kenneth K Oldehinkel Albertine J AJ Ostrowski Sisse R SR Palotie Aarno A Pedersen Ole B OB Peters Annette A Pianigiani Giulia G Plaseska-Karanfilska Dijana D Pouta Anneli A Pozarickij Alfred A Radice Paolo P Rennert Gad G Rosendaal Frits R FR Ruggiero Daniela D Saloustros Emmanouil E Sandler Dale P DP Schipf Sabine S Schmidt Carsten O CO Schmidt Marjanka K MK Small Kerrin K Spedicati Beatrice B Stampfer Meir M Stone Jennifer J Tamimi Rulla M RM Teras Lauren R LR Tikkanen Emmi E Turman Constance C Vachon Celine M CM Wang Qin Q Winqvist Robert R Wolk Alicja A Zemel Babette S BS Zheng Wei W van Dijk Ko W KW Alizadeh Behrooz Z BZ Bandinelli Stefania S Boerwinkle Eric E Boomsma Dorret I DI Ciullo Marina M Chenevix-Trench Georgia G Cucca Francesco F Esko Tõnu T Gieger Christian C Grant Struan F A SFA Gudnason Vilmundur V Hayward Caroline C Kolčić Ivana I Kraft Peter P Lawlor Deborah A DA Martin Nicholas G NG Nøhr Ellen A EA Pedersen Nancy L NL Pennell Craig E CE Ridker Paul M PM Robino Antonietta A Snieder Harold H Sovio Ulla U Spector Tim D TD Stöckl Doris D Sudlow Cathie C Timpson Nic J NJ Toniolo Daniela D Uitterlinden André A Ulivi Sheila S Völzke Henry H Wareham Nicholas J NJ Widen Elisabeth E Wilson James F JF Pharoah Paul D P PDP Li Liming L Easton Douglas F DF Njølstad Pål R PR Sulem Patrick P Murabito Joanne M JM Murray Anna A Manousaki Despoina D Juul Anders A Erikstrup Christian C Stefansson Kari K Horikoshi Momoko M Chen Zhengming Z Farooqi I Sadaf IS Pitteloud Nelly N Johansson Stefan S Day Felix R FR Perry John R B JRB Ong Ken K KK

Nature genetics 20240701 7

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, inc ...[more]

PMID: 38951643

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Project description:Heart failure (HF) is a complex trait, influenced by environmental and genetic factors, that affects over 30 million individuals worldwide. Historically, the genetics of HF have been studied in Mendelian forms of disease, where rare genetic variants have been linked to familial cardiomyopathies. More recently, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with risk of HF. However, the relative importance of genetic variants across the allele-frequency spectrum remains incompletely characterized. Here, we report the results of common- and rare-variant association studies of all-cause heart failure, applying recently developed methods to quantify the heritability of HF attributable to different classes of genetic variation. We combine GWAS data across multiple populations including 207,346 individuals with HF and 2,151,210 without, identifying 176 risk loci at genome-wide significance (p < 5×10-8). Signals at newly identified common-variant loci include coding variants in Mendelian cardiomyopathy genes (MYBPC3, BAG3), as well as regulators of lipoprotein (LPL) and glucose metabolism (GIPR, GLP1R), and are enriched in cardiac, muscle, nerve, and vascular tissues, as well as myocyte and adipocyte cell types. Gene burden studies across three biobanks (PMBB, UKB, AOU) including 27,208 individuals with HF and 349,126 without uncover exome-wide significant (p < 3.15×10-6) associations for HF and rare predicted loss-of-function (pLoF) variants in TTN, MYBPC3, FLNC, and BAG3. Total burden heritability of rare coding variants (2.2%, 95% CI 0.99-3.5%) is highly concentrated in a small set of Mendelian cardiomyopathy genes, and is lower than heritability attributable to common variants (4.3%, 95% CI 3.9-4.7%) which is more diffusely spread throughout the genome. Finally, we demonstrate that common-variant background, in the form of a polygenic risk score (PRS), significantly modifies the risk of HF among carriers of pathogenic truncating variants in the Mendelian cardiomyopathy gene TTN. These findings suggest a significant polygenic component to HF exists that is not captured by current clinical genetic testing.

Dataset Information

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

Publications

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

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