TY - JOUR
T1 - Searching for parent-of-origin effects on cardiometabolic traits in imprinted genomic regions
AU - Granot-Hershkovitz, Einat
AU - Wu, Peitao
AU - Karasik, David
AU - Peter, Inga
AU - Peloso, Gina M.
AU - Levy, Daniel
AU - Vasan, Ramachandran S.
AU - Adrienne Cupples, L.
AU - Liu, Ching Ti
AU - Meigs, James B.
AU - Siscovick, David S.
AU - Dupuis, Josée
AU - Friedlander, Yechiel
AU - Hochner, Hagit
N1 - Funding Information:
Funding This study was supported by Israeli Science Foundation grants 201/98-1 and 407/17; partially by NUS-HUJ 370062002, NIH R01HL088884, Samson Family, NHLBI contract HHSN268201500001I, NIDDK R01 DK078616 and K24 DK080140. Genotyping, quality control and calling of the Illumina HumanExome BeadChip used to genotype some of the genetic variants in the FHS was supported by funding from the National Heart, Lung and Blood Institute Division of Intramural Research.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to European Society of Human Genetics.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Cardiometabolic traits pose a major global public health burden. Large-scale genome-wide association studies (GWAS) have identified multiple loci accounting for up to 30% of the genetic variance in complex traits such as cardiometabolic traits. However, the contribution of parent-of-origin effects (POEs) to complex traits has been largely ignored in GWAS. Family-based studies enable the assessment of POEs in genetic association analyses. We investigated POEs on a range of complex traits in 3 family-based studies. The discovery phase was carried out in large pedigrees from the Kibbutzim Family Study (n = 901 individuals) and in 872 parent–offspring trios from the Jerusalem Perinatal Study. Focusing on imprinted genomic regions, we examined parent-specific associations with 12 complex traits (i.e., body-size, blood pressure, lipids), mostly cardiometabolic risk traits. Forty five of the 11,967 SNPs initially found to have POE were evaluated for replication (p value < 1 × 10−4) in Framingham Heart Study families (max n = 8000 individuals). Three common variants yielded evidence of POE in the meta-analysis. Two variants, located on chr6 in the HLA region, showed a paternal effect on height (rs1042136: βpaternal = −0.023, p value = 1.5 × 10−8 and rs1431403: βpaternal = −0.011, p value = 5.4 × 10−6). The corresponding maternally-derived effects were statistically nonsignificant. The variant rs9332053, located on chr13 in RCBTB2 gene, demonstrated a maternal effect on hip circumference (βmaternal = −4.24, p value = 9.6 × 10−6; βpaternal = 1.29, p value = 0.23). These findings provide evidence for the utility of incorporating POEs into association studies of cardiometabolic traits, especially anthropometric traits. The study highlights the benefits of using family-based data for deciphering the genetic architecture of complex traits.
AB - Cardiometabolic traits pose a major global public health burden. Large-scale genome-wide association studies (GWAS) have identified multiple loci accounting for up to 30% of the genetic variance in complex traits such as cardiometabolic traits. However, the contribution of parent-of-origin effects (POEs) to complex traits has been largely ignored in GWAS. Family-based studies enable the assessment of POEs in genetic association analyses. We investigated POEs on a range of complex traits in 3 family-based studies. The discovery phase was carried out in large pedigrees from the Kibbutzim Family Study (n = 901 individuals) and in 872 parent–offspring trios from the Jerusalem Perinatal Study. Focusing on imprinted genomic regions, we examined parent-specific associations with 12 complex traits (i.e., body-size, blood pressure, lipids), mostly cardiometabolic risk traits. Forty five of the 11,967 SNPs initially found to have POE were evaluated for replication (p value < 1 × 10−4) in Framingham Heart Study families (max n = 8000 individuals). Three common variants yielded evidence of POE in the meta-analysis. Two variants, located on chr6 in the HLA region, showed a paternal effect on height (rs1042136: βpaternal = −0.023, p value = 1.5 × 10−8 and rs1431403: βpaternal = −0.011, p value = 5.4 × 10−6). The corresponding maternally-derived effects were statistically nonsignificant. The variant rs9332053, located on chr13 in RCBTB2 gene, demonstrated a maternal effect on hip circumference (βmaternal = −4.24, p value = 9.6 × 10−6; βpaternal = 1.29, p value = 0.23). These findings provide evidence for the utility of incorporating POEs into association studies of cardiometabolic traits, especially anthropometric traits. The study highlights the benefits of using family-based data for deciphering the genetic architecture of complex traits.
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U2 - 10.1038/s41431-019-0568-1
DO - 10.1038/s41431-019-0568-1
M3 - Article
C2 - 31896779
AN - SCOPUS:85077567687
SN - 1018-4813
VL - 28
SP - 646
EP - 655
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 5
ER -