Proposed multigenic Composite Inheritance in major depression.

Abstract

Various rationale have been considered in the familial inheritance pattern of major depression ranging from simple one-gene Mendelian inheritance to pseudo-additive gene action. We instead predict broad genetic expressivity patterns in the progeny of parents where at least one parent has recurrent major depression. In keeping with this idea, we feel that recurrent major depression could involve an expression imbalance of "normal" genes either exclusively or along with allelic variation(s). The patterns of pathology are theoretically conceptualized as qualitative and quantitative, meaning that expressivity of the genetic pattern in these children may range from minimal to complete even among siblings. Thus, prediction of the particular genetic pattern expressed by a particular child might prove difficult. The complex inheritance pattern that we propose is referred to as Composite Inheritance. Composite Inheritance considers that both the up- and down-regulation of luxury genes and housekeeping genes are involved in this dichotomous qualitative inheritance pattern and also the wide quantitative expressivity. The luxury genes include such genes as those coding for the neurotransmitter transporters and receptors. The housekeeping genes found to date include those that code for proteins involved in gene transcription, secondary signaling systems, fatty acid metabolism and transport, and intracellular calcium homeostasis. Other luxury and housekeeping genes no doubt remain to be discovered. Our current research utilizes an empirical approach involving advanced genomics and specialized pattern recognition mathematics in families having at least one parent with recurrent major depression. The goal of our research is to develop a pattern recognition system of genetic expressivity in major depression to which prevention and early intervention may be tailored.