Open Access Highly Accessed Research article

Candidate gene analysis of spontaneous preterm delivery: New insights from re-analysis of a case-control study using case-parent triads and control-mother dyads

Solveig Myking1*, Ronny Myhre1, Håkon K Gjessing12, Nils-Halvdan Morken13, Verena Sengpiel4, Scott M Williams5, Kelli K Ryckman56, Per Magnus1 and Bo Jacobsson14

Author Affiliations

1 Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway

2 Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway

3 Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway

4 Department of Obstetrics and Gynecology, Institute of Clinical Science, Sahlgrenska University Hospital, Göteborg, Sweden

5 Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, USA

6 Department of Pediatrics, University of Iowa, Iowa City, IA, USA

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BMC Medical Genetics 2011, 12:174  doi:10.1186/1471-2350-12-174

Published: 30 December 2011



Spontaneous preterm delivery (PTD) has a multifactorial etiology with evidence of a genetic contribution to its pathogenesis. A number of candidate gene case-control studies have been performed on spontaneous PTD, but the results have been inconsistent, and do not fully assess the role of how two genotypes can impact outcome. To elucidate this latter point we re-analyzed data from a previously published case-control candidate gene study, using a case-parent triad design and a hybrid design combining case-parent triads and control-mother dyads. These methods offer a robust approach to genetic association studies for PTD compared to traditional case-control designs.


The study participants were obtained from the Norwegian Mother and Child Cohort Study (MoBa). A total of 196 case triads and 211 control dyads were selected for the analysis. A case-parent triad design as well as a hybrid design was used to analyze 1,326 SNPs from 159 candidate genes. We compared our results to those from a previous case-control study on the same samples. Haplotypes were analyzed using a sliding window of three SNPs and a pathway analysis was performed to gain biological insight into the pathophysiology of preterm delivery.


The most consistent significant fetal gene across all analyses was COL5A2. The functionally similar COL5A1 was significant when combining fetal and maternal genotypes. PON1 was significant with analytical approaches for single locus association of fetal genes alone, but was possibly confounded by maternal effects. Focal adhesion (hsa04510), Cell Communication (hsa01430) and ECM receptor interaction (hsa04512) were the most constant significant pathways.


This study suggests a fetal association of COL5A2 and a combined fetal-maternal association of COL5A1 with spontaneous PTD. In addition, the pathway analysis implied interactions of genes affecting cell communication and extracellular matrix.

case-parent triad analysis; hybrid design; haplotype; pathway analysis; COL5A2; COL5A1