Abstract
Background
Preterm birth (<37 weeks of gestation) is a major cause of neonatal death and morbidity. Up to 40% of the variation in timing of birth results from genetic factors, mostly due to the maternal genome.
Methods
We conducted a genome-wide meta-analysis of gestational duration and spontaneous preterm birth in 68,732 and 98,370 European mothers, respectively.
Results
The meta-analysis detected 15 loci associated with gestational duration, and four loci associated with preterm birth. Seven of the associated loci were novel. The loci mapped to several biologically plausible genes, for example HAND2 whose expression was previously shown to decrease during gestation, associated with gestational duration, and GC (Vitamin D-binding protein), associated with preterm birth. Downstream in silico-analysis suggested regulatory roles as underlying mechanisms for the associated loci. LD score regression found birth weight measures as the most strongly correlated traits, highlighting the unique nature of spontaneous preterm birth phenotype. Tissue expression and colocalization analysis revealed reproductive tissues and immune cell types as the most relevant sites of action.
Conclusion
We report novel genetic risk loci that associate with preterm birth or gestational duration, and reproduce findings from previous genome-wide association studies. Altogether, our findings provide new insight into the genetic background of preterm birth. Better characterization of the causal genetic mechanisms will be important to public health as it could suggest new strategies to treat and prevent preterm birth.
Funder
Business Finland
AbbVie
AstraZeneca UK
Biogen
Bristol-Myers Squibb
Genentech
Merck Sharp and Dohme
Pfizer Inc
GlaxoSmithKline Intellectual Property Development Ltd
Sanofi
Maze Therapeutics
Janssen Biotech
Novartis AG
Boehringer Ingelheim
Jane ja Aatos Erkon Säätiö
Competitive State Research Financing of the Expert Responsibility Area of Oulu University Hospital
Sigrid Juséliuksen Säätiö
Lastentautien Tutkimussäätiö
Emil Aaltosen Säätiö
Stiftelsen Alma och K. A. Snellman Säätiö
Oak Foundation Fellowship
Novo Nordisk Foundation
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Burroughs Wellcome Fund
March of Dimes Prematurity Research Center Ohio Collaborative
Bill and Melinda Gates Foundation
Norwegian Ministry of Health and the Ministry of Education and Research
National Institute of Environmental Health Sciences
National Institute of Neurological Disorders and Stroke
Norwegian Research Council/FUGE
Swedish Research Council
Norwegian Research Council
Jane och Dan Olssons Stiftelse
Swedish government to researchers in the public health service
Danish National Research Foundation
Danish Regional Committees, the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Health Foundation
Lundbeck Foundation
Publisher
Public Library of Science (PLoS)
Subject
Cancer Research,Genetics (clinical),Genetics,Molecular Biology,Ecology, Evolution, Behavior and Systematics