title: Mapping a new spontaneous preterm birth susceptibility gene, IGF1R, using linkage, haplotype sharing, and association analysis.
abstract: Preterm birth is the major cause of neonatal death and serious morbidity. Most preterm births are due to spontaneous onset of labor without a known cause or effective prevention. Both maternal and fetal genomes influence the predisposition to spontaneous preterm birth (SPTB), but the susceptibility loci remain to be defined. We utilized a combination of unique population structures, family-based linkage analysis, and subsequent case-control association to identify a susceptibility haplotype for SPTB. Clinically well-characterized SPTB families from northern Finland, a subisolate founded by a relatively small founder population that has subsequently experienced a number of bottlenecks, were selected for the initial discovery sample. Genome-wide linkage analysis using a high-density single-nucleotide polymorphism (SNP) array in seven large northern Finnish non-consanginous families identified a locus on 15q26.3 (HLOD 4.68). This region contains the IGF1R gene, which encodes the type 1 insulin-like growth factor receptor IGF-1R. Haplotype segregation analysis revealed that a 55 kb 12-SNP core segment within the IGF1R gene was shared identical-by-state (IBS) in five families. A follow-up case-control study in an independent sample representing the more general Finnish population showed an association of a 6-SNP IGF1R haplotype with SPTB in the fetuses, providing further evidence for IGF1R as a SPTB predisposition gene (frequency in cases versus controls 0.11 versus 0.05, P = 0.001, odds ratio 2.3). This study demonstrates the identification of a predisposing, low-frequency haplotype in a multifactorial trait using a well-characterized population and a combination of family and case-control designs. Our findings support the identification of the novel susceptibility gene IGF1R for predisposition by the fetal genome to being born preterm.
authors.affiliation: Department of Pediatrics, Institute of Clinical Medicine, University of Oulu, Oulu, Finland.
authors.forename: Ritva
authors.initials: R
authors.lastname: Haataja
authors.forename: Minna K
authors.initials: MK
authors.lastname: Karjalainen
authors.forename: Aino
authors.initials: A
authors.lastname: Luukkonen
authors.forename: Kari
authors.initials: K
authors.lastname: Teramo
authors.forename: Hilkka
authors.initials: H
authors.lastname: Puttonen
authors.forename: Marja
authors.initials: M
authors.lastname: Ojaniemi
authors.forename: Teppo
authors.initials: T
authors.lastname: Varilo
authors.forename: Bimal P
authors.initials: BP
authors.lastname: Chaudhari
authors.forename: Jevon
authors.initials: J
authors.lastname: Plunkett
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Steven A
authors.initials: SA
authors.lastname: McCarroll
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Muglia
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Mikko
authors.initials: M
authors.lastname: Hallman
mesh_terms: D016022:Case-Control Studies; D005260:Female; D005387:Finland; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000235:genetics*
chemical_list: D017526:Receptor, IGF Type 1