Amish Connectome Project on Mental Illness



 DESCRIPTION (provided by applicant): The Amish Connectome Project (ACP) will extend the Human Connectome Project (HCP) to mental illnesses by characterizing brain circuitry and its relation to psychiatric behavior and symptom dimensions. We propose to collect HCP connectomics and whole genome sequencing data in Old Order Amish (OOA) adults recruited from multigenerational families with multiplex mental disorders spanning diagnostic boundaries. Large nuclear families with two or more members with major DSM-5 disorder will be recruited for phenotyping using the full HCP lifespan imaging and behavioral protocol expanded to Research Domain Criteria (RDoC) standard. The advent of non-invasive connectivity-oriented neuroimaging methods has shed new light onto the inner workings of the brain. The brain's functional and structural connectome plays key roles in regulating the pathway from genes to neural systems to mental illnesses. Extending the gene -->connectome HCP approach to gene -->connectome -->mental disorder in HCP-Human Disease adds tremendous opportunity to identify genetic underpinning of heritable mental disorders. ACP offers a uniquely efficient and powerful study design that is critical for a successful breakthrough. The ACP will study large, multigenerational families from a population isolate, which is a powerful statistical design for discovery of genetic linkage between connectomic traits and mental disorders. The OOA sample is unique in its relative genetic uniformity, with ancestry recorded in the NIH database and traceable back fourteen generations to limited founders. This sample is also unique because of its relative uniformity in educational background, life and work conditions, socioeconomic status and much reduced influence by illicit drugs. These unique characteristics of OOA community members, combined with their large family size, makes the OOA a powerful population sample to study the genetic factors that alter cerebral connectivity in mental disorders with familial pattern of inheritance. We will expand upon HCP protocol with the psychiatric diagnosis, broad symptom and RDoC dimensional assessments of behavior and cognition. Whole genome data will be obtained for all participants through next generation sequencing and family-based imputation of GWAS data. These data will be shared with the large research community while protecting the privacy, confidentiality and welfare of participants, with special attention given to protect the welfare of the OOA community. Medical genetic discoveries in OOA have routinely been replicated in general population samples and translated to clinical practice. We are inspired to create opportunities to allow repetitions of suh success in brain connectome and in mental illness through shared data effort, and have assembled an efficient team to lead this endeavor.