Mapping a New Spontaneous Preterm Birth Susceptibility Gene, IGF1R, Using Linkage, Haplotype Sharing, and Association Analysis
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...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Public Library of Science
2011
|
| Online Access: | http://hdl.handle.net/1721.1/64462 |
| _version_ | 1811084591549644800 |
|---|---|
| author | Haataja, Ritva Karjalainen, Minna K. Luukkonen, Aino Teramo, Kari Puttonen, Hilkka Ojaniemi, Marja Varilo, Teppo Chaudhari, Bimal P. Murray, Jeffrey C. McCarroll, Steven A. Peltonen, Leena Muglia, Louis J. Palotie, Aarno Hallman, Mikko Plunkett, Jevon |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard Haataja, Ritva Karjalainen, Minna K. Luukkonen, Aino Teramo, Kari Puttonen, Hilkka Ojaniemi, Marja Varilo, Teppo Chaudhari, Bimal P. Murray, Jeffrey C. McCarroll, Steven A. Peltonen, Leena Muglia, Louis J. Palotie, Aarno Hallman, Mikko Plunkett, Jevon |
| author_sort | Haataja, Ritva |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T12:53:33Z |
| format | Article |
| id | mit-1721.1/64462 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:53:33Z |
| publishDate | 2011 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/644622022-09-28T10:42:41Z Mapping a New Spontaneous Preterm Birth Susceptibility Gene, IGF1R, Using Linkage, Haplotype Sharing, and Association Analysis Haataja, Ritva Karjalainen, Minna K. Luukkonen, Aino Teramo, Kari Puttonen, Hilkka Ojaniemi, Marja Varilo, Teppo Chaudhari, Bimal P. Murray, Jeffrey C. McCarroll, Steven A. Peltonen, Leena Muglia, Louis J. Palotie, Aarno Hallman, Mikko Plunkett, Jevon Broad Institute of MIT and Harvard Peltonen, Leena Peltonen, Leena Palotie, Aarno 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. Academy of Finland. Center of Excellence for Complex Disease Genetics (200923) National Center for Research Resources (U.S.) National Center for Research Resources (U.S.) (grant U54 RR020278) Wellcome Trust (London, England) (WTO89062) 2011-06-16T18:14:13Z 2011-06-16T18:14:13Z 2011-02 2010-08 Article http://purl.org/eprint/type/JournalArticle 1553-7404 1553-7390 http://hdl.handle.net/1721.1/64462 Haataja Ritva et al. "Mapping a New Spontaneous Preterm Birth Susceptibility Gene, IGF1R, Using Linkage, Haplotype Sharing, and Association Analysis." PLoS Genet (2011) 7(2): e1001293. en_US http://dx.doi.org/10.1371/journal.pgen.1001293 PLoS Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Haataja, Ritva Karjalainen, Minna K. Luukkonen, Aino Teramo, Kari Puttonen, Hilkka Ojaniemi, Marja Varilo, Teppo Chaudhari, Bimal P. Murray, Jeffrey C. McCarroll, Steven A. Peltonen, Leena Muglia, Louis J. Palotie, Aarno Hallman, Mikko Plunkett, Jevon Mapping a New Spontaneous Preterm Birth Susceptibility Gene, IGF1R, Using Linkage, Haplotype Sharing, and Association Analysis |
| title | Mapping a New Spontaneous Preterm Birth Susceptibility Gene, IGF1R, Using Linkage, Haplotype Sharing, and Association Analysis |
| title_full | Mapping a New Spontaneous Preterm Birth Susceptibility Gene, IGF1R, Using Linkage, Haplotype Sharing, and Association Analysis |
| title_fullStr | Mapping a New Spontaneous Preterm Birth Susceptibility Gene, IGF1R, Using Linkage, Haplotype Sharing, and Association Analysis |
| title_full_unstemmed | Mapping a New Spontaneous Preterm Birth Susceptibility Gene, IGF1R, Using Linkage, Haplotype Sharing, and Association Analysis |
| title_short | Mapping a New Spontaneous Preterm Birth Susceptibility Gene, IGF1R, Using Linkage, Haplotype Sharing, and Association Analysis |
| title_sort | mapping a new spontaneous preterm birth susceptibility gene igf1r using linkage haplotype sharing and association analysis |
| url | http://hdl.handle.net/1721.1/64462 |
| work_keys_str_mv | AT haatajaritva mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT karjalainenminnak mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT luukkonenaino mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT teramokari mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT puttonenhilkka mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT ojaniemimarja mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT variloteppo mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT chaudharibimalp mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT murrayjeffreyc mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT mccarrollstevena mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT peltonenleena mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT muglialouisj mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT palotieaarno mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT hallmanmikko mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis AT plunkettjevon mappinganewspontaneouspretermbirthsusceptibilitygeneigf1rusinglinkagehaplotypesharingandassociationanalysis |