Genetic regulation of the placental transcriptome underlies birth weight and risk of childhood obesity

Abstract

GWAS identified variants associated with birth weight (BW), childhood obesity (CO) and childhood BMI (CBMI), and placenta is a critical organ for fetal development and postnatal health. We examined the role of placental transcriptome and eQTLs in mediating the genetic causes for BW, CO and CBMI, and applied integrative analysis (Colocalization and MetaXcan). GWAS loci associated with BW, CO, and CBMI were substantially enriched for placenta eQTLs (6.76, 4.83 and 2.26 folds, respectively). Importantly, compared to eQTLs of adult tissues, only placental eQTLs contribute significantly to both anthropometry outcomes at birth (BW) and childhood phenotypes (CO/CBMI). Eight, six and one transcripts colocalized with BW, CO and CBMI risk loci, respectively. Our study reveals that placental transcription in utero likely plays a key role in determining postnatal body size, and as such may hold new possibilities for therapeutic interventions to prevent childhood obesity.

Fig 1. Enrichment of small pvalues for RICHS placenta tissue eSNPs and for eSNPs of adult tissues (STARNET cohort, Materials and methods) in A, birth weight (BW), B, childhood obesity (CO), and C, childhood body mass index (CBMI) GWASes.

Adult tissues: blood, atherosclerotic-lesion-free internal mammary artery (MAM), atherosclerotic aortic root (AOR), subcutaneous fat (SF), visceral abdominal fat (VAF), skeletal muscle (SKLM), and liver (LIV).

Fig 2. A, LocusZoom plots of BW GWAS peak with lead SNP rs2421016 (chr10:124167512). B, C, D, E, LocusZoom plots of eQTL peaks on PLEKHA1, HTRA1, ARMS2, BTBD16 genes, respectively.

In these plots, each dot denotes a variant. Purple dots: lead SNP chr10:124167512; red and orange dots, SNPs of strong LD (r²>0.6) with lead SNP; green and light blue dots, SNPs of moderate LD (0.6>r²>0.2) with the lead SNP; and dark blue dots, SNPs of weak or no LD (r²<0.2) with the lead SNP.