Using the high-risk family design to identify biomarkers for major depression.

The familial nature of major depressive disorder (MDD) is now well recognized. We followed children and grandchildren of probands with and without MDD to examine transmission of depression over generations, and to identify early vulnerability markers prior to the onset of disease. The study now includes three generations and five completed assessment waves spanning 25 years, with a sixth wave underway. Beginning with the fourth wave, we collected measures of brain structure (magnetic resonance imaging, MRI) and physiology (electroencephalography, EEG) and DNA in order to examine at a biological level why the offspring of depressed parents were at higher risk. In this paper, we provide an overview of the study design, the main findings, including new data, and the role of the high-risk design in translational research. We demonstrate that offspring of depressed parents ('high-risk'), when compared with those of non-depressed parents ('low-risk'), were at increased risk for depressive and anxiety disorders, with anxiety appearing earlier and being a predisposing factor for MDD. Offspring with two generations previously affected were at greatest risk. Thinning of the cortical mantle (MRI) and reduced resting-state activity (EEG) within the right parieto-temporal hemisphere differentiated high- from low-risk offspring, regardless of whether the offspring had MDD, suggesting that these measures might serve as familial trait markers for depression and related syndromes. The high- and low-risk offspring also differed by serotonin transporter promoter length polymorphism genotypes, even though the same genotypes were not associated with the presence of MDD. The high-risk epidemiological design appears to be a particularly valuable asset in translational research as it allows targeting of biological processes that emerge prior to the onset of disease, and identifies individuals at high risk for the disorder who may carry the trait or marker but not yet be affected.