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

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.Author summary: Genetic studies (e.g GWAS) revealed substantial heritability on birth weight (BW), childhood obesity (CO) and childhood body mass index (CBMI), however, the etiological mechanisms and relevant tissue(s) underlying these traits/conditions are not clear. We incorporated the data from largest GWASes to date and placenta expressional quantitative trait loci (eQTL) that have been newly published, and showed the variants 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 in 7 adult tissues such as adipose and liver, only eQTLs in the placenta were found to contribute significantly not only to anthropometry outcomes at birth (BW) but also to childhood phenotypes (CO/CBMI). Further, we employed COLOC and MetaXcan analyses and identified placenta transcripts potential mediate the genetic effect of BW/CO/CBMI GWAS loci. In summary, our study strongly supports a key role for the placenta in determining BW, CO and CMBI at the molecular level, and pinpointed genes whose expression levels in placenta potentially influences BW and CO risk.