Evolutionary Triangulation to Refine Genetic Association Studies of Spontaneous Preterm Birth

Tracy A. Manuck; Minjun Huang; Louis Muglia; Scott M. Williams

doi:10.1055/s-0037-1603508

American Journal of Perinatology, Table of Contents

Am J Perinatol 2017; 34(11): 1041-1047
DOI: 10.1055/s-0037-1603508

Original Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Evolutionary Triangulation to Refine Genetic Association Studies of Spontaneous Preterm Birth

Tracy A. Manuck

¹Department of Obstetrics & Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

,

Minjun Huang

²Department of Molecular and Systems Biology, Dartmouth College, Hanover, New Hampshire

,

Louis Muglia

³Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, Ohio

,

Scott M. Williams

⁴Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio

› Author Affiliations

Abstract

Objective The objective of this study was to apply evolutionary triangulation, a novel technique exploiting evolutionary differentiation among three populations with variable disease prevalence, to spontaneous preterm birth (PTB) genetic association studies.

Study Design Single nucleotide polymorphism (SNP) allele frequency data were obtained from HapMap for CEU, GIH/MEX, and YRI/ASW populations. Evolutionary triangulation SNPs, then genes, were selected according to the overlaps of genetic population differences (CEU = outlier). Evolutionary triangulation genes were then compared with three PTB gene lists: (1) top maternal and fetal genes from a large genome-wide association study of PTB, (2) 640 genes from the database for PTB, and (3) 118 genes from a recent systematic review. Empirical p-values were calculated to determine whether evolutionary triangulation enriched for putative PTB associating genes compared with randomly selected sample genes.

Results Evolutionary triangulation identified 5/17 maternal genes and 8/16 fetal genes from PTB gene list 1. From list 2, 79/640 were identified by CEU_GIH_YRI evolutionary triangulation, and 57/640 were identified by CEU_ASW_MEX evolutionary triangulation. Finally, 20/118 genes were identified by evolutionary triangulation from gene list 3. For all analyses, p < 0.001 except CEU_ASW_MEX analysis of list 3 where p = 0.002.

Conclusion Genes identified in prior PTB association studies confirmed by evolutionary triangulation should be prioritized for further genetic prematurity research.

Keywords

preterm birth - evolutionary triangulation - genetic - susceptibility - racial disparity

Full Text

References

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