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

Abstract

One contribution of 11 to a Theme Issue 'The neurobiology of depression-revisiting the serotonin hypothesis. II. Genetic, epigenetic and clinical studies'. 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.

Trajectories of individual depressive symptoms in adolescents: Gender and family relationships as predictors.

“…The findings may not generalize to other racial or ethnic groups, to a purely community sample, or to adolescents whose parents have psychopathology other than depression. Nevertheless, the high risk research design is used frequently among researchers investigating depression in adolescents (e.g., Abela et al, 2005; Lau, Rijsdijk, Gregory, McGuffin, & Eley, 2007; Talati, Weissman, & Hamilton, 2013). Studying offspring of individuals with a particular disorder is recommended when trying to identify risk factors associated with the disorder, particularly prior to its onset (Ingram & Siegle, 2009).…”

Motivated attention and family risk for depression: Neuronal generator patterns at scalp elicited by lateralized aversive pictures reveal blunted emotional responsivity

“…Participants were enrolled in a multi-generation, 30-year longitudinal study of families at high and low risk for major depression that employed stringent selection and assessment procedures as detailed elsewhere (Talati et al, 2013, Weissman et al, 2016a, Weissman et al, 2016b). Briefly, probands were initially selected for the presence or absence of a lifetime history of major depressive disorder (MDD) from outpatient psychiatric clinics and their urban community in New Haven, CT (Weissman et al, 1982, Weissman et al, 1992).…”

“…Offspring and grandchildren of depressed patients are at increased risk for developing depressive and anxiety disorders (e.g., Talati et al, 2013, Weissman et al, 2016a). In agreement with EEG findings at rest for MDD patients (e.g., Bruder et al, 1997), descendants of probands with MDD, compared to those without, had greater alpha activity over right than left parietal regions, presumed to indicate reduced right parietal activation (Bruder et al, 2005, Bruder et al, 2007).…”

“…Such findings would further support the idea that hypoarousal of right temporoparietal cortex and other emotional brain regions in response to affective stimuli may reflect an endophenotype of depression indicative of a deficit in motivated attention, which could be helpful in identifying more specific treatments and prevention strategies for familial depression (Moratti et al, 2015). The design and longitudinal nature of the high-risk study (Talati et al, 2013, Weissman et al, 2016a, Weissman et al, 2016b) also enabled us to examine the impact of lifetime diagnosis of depressive or anxiety disorders on emotional ERP effects. We expected that individuals having a lifetime history of MDD would be particularly likely to show blunted emotional ERP responses along with overall LPP reductions.…”

The neurobiology of depression—revisiting the serotonin hypothesis. II. Genetic, epigenetic and clinical studies

“…Genetic transmission is a recognized factor in depression and heritability runs at about 40 per cent for major depression [6]. The studies presented by Talati and co-workers [7] reminds the readership that the risk for depression can be transmitted over generations, and a major part of this transmission is due to genetic transmission from parents to offspring. The family cohorts collected by this group offer perhaps the strongest genetically related group with potentially greater homogeneity for identifying significant linkage between specific genetic loci and depression using high-throughput genome sequence analysis.…”