Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis
Võsa U., Claringbould A., Westra H-J., Bonder MJ., Deelen P., Zeng B., Kirsten H., Saha A., Kreuzhuber R., Kasela S., Pervjakova N., Alvaes I., Fave M-J., Agbessi M., Christiansen M., Jansen R., Seppälä I., Tong L., Teumer A., Schramm K., Hemani G., Verlouw J., Yaghootkar H., Sönmez R., Brown A., Kukushkina V., Kalnapenkis A., Rüeger S., Porcu E., Kronberg-Guzman J., Kettunen J., Powell J., Lee B., Zhang F., Arindrarto W., Beutner F., Brugge H., Dmitreva J., Elansary M., Fairfax BP., Georges M., Heijmans BT., Kähönen M., Kim Y., Knight JC., Kovacs P., Krohn K., Li S., Loeffler M., Marigorta UM., Mei H., Momozawa Y., Müller-Nurasyid M., Nauck M., Nivard M., Penninx B., Pritchard J., Raitakari O., Rotzchke O., Slagboom EP., Stehouwer CDA., Stumvoll M., Sullivan P., Hoen PACT., Thiery J., Tönjes A., van Dongen J., van Iterson M., Veldink J., Völker U., Wijmenga C., Swertz M., Andiappan A., Montgomery GW., Ripatti S., Perola M., Kutalik Z., Dermitzakis E., Bergmann S., Frayling T., van Meurs J., Prokisch H., Ahsan H., Pierce B., Lehtimäki T., Boomsma D., Psaty BM., Gharib SA., Awadalla P., Milani L., Ouwehand W., Downes K., Stegle O., Battle A., Yang J., Visscher PM., Scholz M., Gibson G., Esko T., Franke L.
SummaryWhile many disease-associated variants have been identified through genome-wide association studies, their downstream molecular consequences remain unclear.To identify these effects, we performedcis-andtrans-expressionquantitative trait locus (eQTL) analysis in blood from 31,684 individuals through the eQTLGen Consortium.We observed thatcis-eQTLs can be detected for 88% of the studied genes, but that they have a different genetic architecture compared to disease-associated variants, limiting our ability to usecis-eQTLs to pinpoint causal genes within susceptibility loci.In contrast, trans-eQTLs (detected for 37% of 10,317 studied trait-associated variants) were more informative. Multiple unlinked variants, associated to the same complex trait, often converged on trans-genes that are known to play central roles in disease etiology.We observed the same when ascertaining the effect of polygenic scores calculated for 1,263 genome-wide association study (GWAS) traits. Expression levels of 13% of the studied genes correlated with polygenic scores, and many resulting genes are known to drive these traits.