Project Summary People with Down syndrome (Ds), and other intellectual and developmental disabilities (IDD), are at greater risk for stressful life experiences and depression than the general population, yet are less likely to be diagnosed and receive appropriate treatment. The lack of validated assessment tools for this population is a major impediment to research, diagnosis, and treatment of depression for people with Ds. The overarching goal of this K08 proposal is to provide the candidate, who is a clinical psychologist, with the training, mentorship, and research opportunities necessary to combine psychometric and genomic research methodologies to study biomarkers of stress and depression in populations that are challenging to assess, thus supporting the candidate's long-term goal of conducting federally-funded genomically-informed measurement research in people with Ds and other forms of IDD. The candidate and mentorship team have created a comprehensive training plan including coursework, intensive mentoring, summer programs, and conferences in Ds-related developmental and psychiatric phenotypes, statistics, and epigenetic biomarkers. The multidisciplinary mentorship team is comprised of leading experts: Dr. Colleen Jackson-Cook (clinical cytogeneticist and medical geneticist; primary mentor), a leading expert in epigenetics and cytogenetics of Ds; Dr. Ananda Amstadter (clinical psychologist; co-mentor), an expert in stress and depression; and Dr. George Capone (co-mentor), an expert in Ds developmental phenotypes. The mentorship team is rounded out by Dr. Accardo, board certified developmental pediatrician with expertise in developmental disabilities, and Drs. Aggen, and York, who provide expertise in phenotype measurement, statistical genetics, and bioinformatics. The candidate will apply the acquired skills by conducting a multistage, multi-method measurement study of stressful life events and depression in people with Ds. The first stage will involve the preliminary psychometric analyses of self-report, caregiver-report, and clinical diagnostic data from a sample of 75 participants with mosaic Ds (mDs), whose higher cognitive and verbal functioning can provide a “window” into the social and emotional experiences of people with Ds. This data will be used for measure refinement for deployment in the second stage in which the refined assessments will be administered and validated within a sample of 100 participants with complete (non-mosaic) Ds. The third stage will involve a comparison of genome-wide methylation and telomere length in participants with complete Ds diagnosed with depression (cases; n=25) and without (controls; n=25) to identify potential biomarkers of depression. Furthermore, the role of stressful life events will be explored in the biological embedding of depression. The identification of these biomarkers will not only complement the validation of patient-reported assessment tools, they may also serve as cost-effective diagnostic tools in their own right and play a vital role in differential diagnosis and future research on pharmacological and psychosocial treatments for depression in this population.

Project Narrative This K08 award will provide the candidate with the training necessary to pursue a multimodal program of research, including the development of assessment tools for depression and stressful life events and the incorporation of clinical and biomarker data to better identify depression in people with Down syndrome (Ds). Given that depressive symptoms are modifiable via psychosocial or pharmacologic intervention, the development of tools to facilitate the recognition of depression in people with Ds could lead to advances in research aimed at reducing the risk (or progression) of depression in this highly vulnerable population.