| Title: |
Understanding the genetic complexity of puberty timing across the allele frequency spectrum |
| Authors: |
ABCTB Investigators; The Lifelines Cohort Study; The Danish Blood Donor Study; The Biobank Japan Project; the China Kadoorie Biobank Collaborative Group; Kentistou, Katherine A.; Kaisinger, Lena R.; Stankovic, Stasa; Järvelin, Marjo Riitta; Eriksson, Johan G.; Nevanlinna, Heli; Palotie, Aarno; Tikkanen, Emmi; Widen, Elisabeth |
| Contributors: |
Clinicum; Research Programs Unit; Johan Eriksson / Principal Investigator; Department of General Practice and Primary Health Care; University of Helsinki; HUS Group; HUS Gynecology and Obstetrics; Department of Obstetrics and Gynecology; Aarno Palotie / Principal Investigator; Institute for Molecular Medicine Finland; Genomics of Neurological and Neuropsychiatric Disorders; Centre of Excellence in Complex Disease Genetics; Elisabeth Ingrid Maria Widen / Principal Investigator; Genomic Discoveries and Clinical Translation |
| Publisher Information: |
Nature Research |
| Publication Year: |
2025 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
Genetics; developmental biology; physiology |
| Description: |
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 reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
This research was supported by the UK Medical Research Council (MRC; Unit program MC_UU_00006/2) and has been conducted using the UK Biobank Resource under application 9905. Other study-specific acknowledgements can be found in the .; https://hdl.handle.net/10138/591419; 85199125224; 001287294200002 |
| Availability: |
https://hdl.handle.net/10138/591419 |
| Rights: |
cc_by ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.E8471833 |
| Database: |
BASE |