A valuable approach to understand how individual and population genetic 
differences can predispose to disease is to assess the impact of genetic 
variants on cellular functions (e.g., gene expression) of cell and tissue types 
related to pathological states. To understand the genetic basis of nonsyndromic 
cleft lip with or without cleft palate (NSCL/P) susceptibility, a complex and 
highly prevalent congenital malformation, we searched for genetic variants with 
a regulatory role in a disease-related tissue, the lip muscle (orbicularis oris 
muscle [OOM]), of affected individuals. From 46 OOM samples, which are 
frequently discarded during routine corrective surgeries on patients with 
orofacial clefts, we derived mesenchymal stem cells and correlated the 
individual genetic variants with gene expression from these cultured cells. 
Through this strategy, we detected significant cis-eQTLs (i.e., DNA variants 
affecting gene expression) and selected a few candidates to conduct an 
association study in a large Brazilian cohort (624 patients and 668 controls). 
This resulted in the discovery of a novel susceptibility locus for NSCL/P, 
rs1063588, the best eQTL for the MRPL53 gene, where evidence for association was 
mostly driven by the Native American ancestry component of our Brazilian sample. 
MRPL53 (2p13.1) encodes a 39S protein subunit of mitochondrial ribosomes and 
interacts with MYC, a transcription factor required for normal facial 
morphogenesis. Our study illustrates not only the importance of sampling admixed 
populations but also the relevance of measuring the functional effects of 
genetic variants over gene expression to dissect the complexity of disease 
phenotypes.