Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.
Liu X., Helenius D., Skotte L., Beaumont RN., Wielscher M., Geller F., Juodakis J., Mahajan A., Bradfield JP., Lin FTJ., Vogelezang S., Bustamante M., Ahluwalia TS., Pitkänen N., Wang CA., Bacelis J., Borges MC., Zhang G., Bedell BA., Rossi RM., Skogstrand K., Peng S., Thompson WK., Appadurai V., Lawlor DA., Kalliala I., Power C., McCarthy MI., Boyd HA., Marazita ML., Hakonarson H., Hayes MG., Scholtens DM., Rivadeneira F., Jaddoe VWV., Vinding RK., Bisgaard H., Knight BA., Pahkala K., Raitakari O., Helgeland Ø., Johansson S., Njølstad PR., Fadista J., Schork AJ., Nudel R., Miller DE., Chen X., Weirauch MT., Mortensen PB., Børglum AD., Nordentoft M., Mors O., Hao K., Ryckman KK., Hougaard DM., Kottyan LC., Pennell CE., Lyytikainen L-P., Bønnelykke K., Vrijheid M., Felix JF., Lowe WL., Grant SFA., Hyppönen E., Jacobsson B., Jarvelin M-R., Muglia LJ., Murray JC., Freathy RM., Werge TM., Melbye M., Buil A., Feenstra B.
The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.