Clotting factor genes are associated with preeclampsia in high-altitude pregnant women in the Peruvian Andes

Abstract

Preeclampsia is a multi-organ complication of pregnancy characterized by sudden hypertension and proteinuria that is among the leading causes of preterm delivery and maternal morbidity and mortality worldwide. The heterogeneity of preeclampsia poses a challenge for understanding its etiology and molecular basis. Intriguingly, risk for the condition increases in high-altitude regions such as the Peruvian Andes. To investigate the genetic basis of preeclampsia in a population living at high altitude, we characterized genome-wide variation in a cohort of preeclamptic and healthy Andean families (n = 883) from Puno, Peru, a city located above 3,800 meters of altitude. Our study collected genomic DNA and medical records from case-control trios and duos in local hospital settings. We generated genotype data for 439,314 SNPs, determined global ancestry patterns, and mapped associations between genetic variants and preeclampsia phenotypes. A transmission disequilibrium test (TDT) revealed variants near genes of biological importance for placental and blood vessel function. The top candidate region was found on chromosome 13 of the fetal genome and contains clotting factor genes PROZ, F7, and F10. These findings provide supporting evidence that common genetic variants within coagulation genes play an important role in preeclampsia. A selection scan revealed a potential adaptive signal around the ADAM12 locus on chromosome 10, implicated in pregnancy disorders. Our discovery of an association in a functional pathway relevant to pregnancy physiology in an understudied population of Native American origin demonstrates the increased power of family-based study design and underscores the importance of conducting genetic research in diverse populations.

Keywords: Andean; GWAS; PROZ; Peru; family trio; offspring genome; preeclampsia; pregnancy.

Figure 1

Location and population structure of the Puno preeclampsia cohort (A) Approximate location and altitude of Puno, Peru. (B) Principal components analysis including PRE-affected individuals, PUN and UNA control subjects, and five continental reference populations from the 1000 Genomes. Inset zoom shows Puno cohort individuals only. (C) ADMIXTURE analysis results showing unsupervised clustering models assuming K = 4 and K = 6. At K = 6 a Puno-specific sub-continental ancestry component not shared with 1KG Peruvians from Lima appears in the Puno cohort, shown here in dark blue.

Figure 2

Top associations from trio analyses by TDT and TDT-POO (A) Manhattan plot showing top association with preeclampsia in the offspring genome: SNP rs5960 on chromosome 13 at p < 10E−05 suggestive of significance shown in red. Horizonal lines indicate top 1% (red) and 5% (blue) significance thresholds of p = 8.E−06 and p = 3.E−05, respectively, as determined by permutation approach. (B) Locus Zoom plot depicting the top associated SNP cluster from the TDT on chromosome 13. (C) Locus Zoom plot depicting the top paternal region from TDT-POO analysis on chromosome 13.

Figure 3

iHS hits across ADAM12 and its closest neighbor, FANK1, on chromosome 10 Genetic positions, exons (vertical bars), introns (horizontal bars), and the direction of transcription (arrows) are shown in the panel below. A signal of selection encompassed by two SNPs (red dots) falls in an intronic region on ADAM12 in case founders (PRE). This signal is weaker in control individuals (UNA).

Figure 4

Manhattan plot showing top association in the maternal genome with diastolic blood pressure SNP rs1874237 on chromosome 4 at p = 3.03E−08 shown in red. Horizonal lines indicate standard genome-wide significance (p = 5E−08 in red) and suggestive thresholds (p = 1E−05) commonly used in the literature.