Exome sequencing in pooled DNA samples to identify maternal pre-eclampsia risk variants

Area of Science:

• Genetics
• Obstetrics
• Evolutionary Medicine

Background:

• Pre-eclampsia is a significant cause of maternal and perinatal mortality.
• Genetic variants predisposing to pre-eclampsia may be under negative evolutionary selection, keeping their population frequencies low.

Purpose of the Study:

• To screen for low-frequency, large-effect genetic risk variants for pre-eclampsia in a Finnish population.
• To investigate the association of selected variants with pre-eclampsia and related quantitative traits.

Main Methods:

• Exome sequencing of pooled samples from Finnish pre-eclamptic women.
• Filtering and genotyping of 28 selected low-frequency variants in a larger cohort.
• Association analysis using reference data from the SISu project for increased statistical power.

Main Results:

• Twenty-eight low-frequency missense, nonsense, and splice site variants were identified and enriched in pre-eclamptic pools.
• None of the tested variants reached genome-wide significance in association analyses with pre-eclampsia.

Conclusions:

• The genetic risk for pre-eclampsia is likely complex, even in a genetically isolated population like Finland.
• Larger sample sizes are required to detect pre-eclampsia risk variants with greater statistical power.