title: Time-Variant Genetic Effects as a Cause for Preterm Birth: Insights from a Population of Maternal Cousins in Sweden.
abstract: Preterm delivery (PTD) is the leading cause of neonatal mortality worldwide, yet its etiology remains largely unexplained. We propose that the genetic factors controlling this trait could act in a nonuniform manner during pregnancy, with each factor having a unique "window of sensitivity." We test this hypothesis by modeling the distribution of gestational ages (GAs) observed in maternal cousins from the Swedish Medical Birth Register (MBR) (n= 35,541 pairs). The models were built using a time-to-event framework, with simulated genetic factors that increase the hazard of birth either uniformly across the pregnancy (constant effect) or only in particular windows (varying effect). By including various combinations of these factors, we obtained four models that were then optimized and compared. Best fit to the clinical data was observed when most of the factors had time-variant effects, independently of the number of loci simulated. Finally, power simulations were performed to assess the ability to discover varying-effect loci by usual methods for genome-wide association testing. We believe that the tools and concepts presented here should prove useful for the design of future studies of PTD and provide new insights into the genetic architecture determining human GA.
authors.affiliation: Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 416 85, Sweden j.juodakis@gmail.com.
authors.forename: Julius
authors.initials: J
authors.lastname: Juodakis
authors.affiliation: Department of Obstetrics and Gynecology, Sahlgrenska University Hospital Östra, 416 85 Gothenburg, Sweden.
authors.forename: Jonas
authors.identifier: 0000-0002-2450-732X
authors.initials: J
authors.lastname: Bacelis
authors.affiliation: Human Genetics Division, Cincinnati Children's Hospital Medical Center, Ohio 45229.|Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Ohio 45229.|March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio 45229.
authors.forename: Ge
authors.identifier: 0000-0002-3077-2568
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Ohio 45229.|March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio 45229.
authors.forename: Louis J
authors.identifier: 0000-0002-0301-8770
authors.initials: LJ
authors.lastname: Muglia
authors.affiliation: Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 416 85, Sweden.|Department of Genetics and Bioinformatics, Area of Health Data and Digitalisation, Norwegian Institute of Public Health, 0473 Oslo, Norway.
authors.forename: Bo
authors.identifier: 0000-0001-5079-2374
authors.initials: B
authors.lastname: Jacobsson
mesh_terms: D003198:Computer Simulation; D005190:Family; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D005865:Gestational Age; D006801:Humans; D008957:Models, Genetic; D036801:Parturition; D047928:Premature Birth / Q000453:epidemiology / Q000235:genetics*; D011336:Probability; D012042:Registries; D013548:Sweden / Q000453:epidemiology; D013997:Time Factors
keywords: Cox regression; genetic simulations; nonproportional hazards; survival analysis