From genetics to mechanism of disease liability

With each advance in genomic technology, new statistical methods have regularly emerged to test genetic hypotheses in complex inheritance, as evidenced throughout this book. Notwithstanding the approach used, the greatest challenge in the genetics of complex traits remains the identification of the gene(s) and the molecular variant(s) accounting for a genetic inference based on statistical testing. We take the example of quantitative trait locus (QTL) mapping for blood pressure (BP) and related phenotypes in rodents to review the current landscape. Traditional approaches to refined mapping are typically hampered by the small effect and the small proportion of the variance attached to individual QTLs. The alternative of functional screens in intact animals, whether by chemical mutagenesis or gene targeting, remains a daunting undertaking. Such limitations account for the slow progress to date of inferences from QTL to gene(s). We select a QTL for differential sodium sensitivity between two mouse inbred lines to propose an approach that can be used in relatively large genomic regions (1) by optimizing the selection of candidate genes and (2) by subjecting such genes to high-throughput functional screens. While this is still work in progress, we think it abundantly illustrates what is ahead of us in delineating genetic variation that underlie complex disease.