Genetic Approaches to Depression: Linkage Studies

Genetic linkage studies provide a means of localizing disease genes to chromosomal regions without any prior knowledge of the underlying pathophysiologic processes and have been used extensively in the study of the genetic basis of illnesses known to be heritable. Linkage studies of depression were initiated in the 1970s and 1980s, with unremarkable results. In the 1990s there were virtually no such studies, although many linkage studies of bipolar disorder were carried out which included family members with depression in the phenotype (illness) definition. In 2003 the results of the first three genome-wide linkage scans of depression were reported. Two of these studies focused on cases of depression with recurrence and early onset of illness, as this subset of cases has a stronger familial component. All three of these studies reported statistically significant linkage findings, though the regions implicated by each (on chromosomes 2q, 12q, and 15q) differed across the studies. These three regions may each contain genes conferring susceptibility to major depression, although replication will be necessary before firm conclusions can be drawn. Further elucidation of the genetic basis of depression will come from linkage studies that employ: larger family samples, more specific clinical subtypes to potentially enhance genetic homogeneity, biological markers as phenotypes (endophenotypes), denser DNA marker maps, and statistical methods that allow for modeling of gene-gene interactions.