Grand Challenge in Behavioral and Psychiatric Genetics: Quantitative Challenges to Keeping Up with Molecular Advances

The historical split between the worlds of quantitative and molecular genetics happened over a century ago and was born of divided emphasis on naturally occurring variation in complex traits and species-typical phenomena (i.e., assuming all members of a species are genetically the same except for a few rogue mutations that disrupt normal processes), respectively (Plomin et al., 2003). This split allowed independent progress to be made in these two different disciplines. Quantitative genetics, through family based designs and animal models considering naturally occurring genetic variation in mice, for example, informed much of what we know about heritability today. Molecular genetics, in contrast, asked whether manipulation of the genetic code, such as " knocking out " a gene, could have an average effect on organisms via altered regulation, under-or over-expression of a gene. Efforts to reconcile the drifting apart of these two approaches began in the 1980s with the advent of DNA markers that, because they were polymorphisms in the DNA itself rather than in a gene product (i.e., red cell blood proteins) held promise for identifying quantitative trait loci (QTLs) responsible for the inheritance of complex traits, such as those in behavioral and psychiatric genetics. However, progress has been slower than expected. In fact, more recent molecular advances point to how quantitative and bioinformatic approaches are lagging behind. This recent advent of new advanced molecular technologies has provided an efficiency in genotyping that allows these two complementary fields of study to synergize to a greater degree. The pace at which information about genetic and epigenetic modification is being produced has created a strain on our available analytic tools when we try to consider the impact or significance of this genetic information. A myriad of molecular techniques exist to characterize rare and common variants, copy number variants (CNVs), and even phase (i.e., the combination of alleles specific to each parental chromosome). This poses a significant challenge to the field as far as integrating the effects of these individual differences to better understand the biological basis of behavior. For example, Lipsky et al. (2009) reported on a number of variants in SLC6A4 (the serot-onin transporter gene) thought to impact expression, yet studies are still being published with only biallelic characterization of 5HTTLPR (a polymorphic region within SLC6A4). Initial evidence suggests that DNA methylation of SLC6A4 (Beach et al., 2011) may also be important. The laboratories publishing biallelic data are frequently not lacking …