FAMILY-BASED STUDIES IN PSYCHIATRIC GENOMICS: PROGRESS AND RELEVANCE IN 2024

Abstract

To our knowledge it is ten years since the last symposium on pedigree-based analyses at the WCPG. In the era of whole genome sequencing a review is timely. As costs fall, the field of psychiatric genomics is transitioning from GWAS to next generation sequencing, with power to expand our understanding of the contribution of rare mutations to genetic burden across disorders. Identified rare pathogenic variants may be more informative in understanding disease biology than the common variants of small effect that represent the majority of discovery to date.

Rare variant association studies require sample sizes an order of magnitude larger than GWAS studies. This is because rare mutations tend to be selected against in populations over a few generations. However, such mutations may be identifiable where multiple generations of the same family are available. Moreover, families do not suffer the same population stratification or other confounds that are present at a population level. This approach, with small sample numbers in a family, allows for detailed phenotypic assessment and is accessible to clinicians and researchers with limited resources who want to contribute to the field.

This symposium will provide an update on progress made in ASD, where significant understanding of the genetic architecture and disease biology is emerging, in part due to trio- and quad-based approaches. We review progress from the PGC Pedigree Sequencing Group with an example of how sequencing individual families, with small numbers of individuals can identify relevant risk mutations only identifiable with thousands of samples using case-control approaches. We describe progress in other adult disorders from the international "Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders" consortium. Finally, we review the findings from colleagues working in India who are applying pedigree-based sequencing study approaches across disorders. Across presentations we consider recruitment, and how emerging findings indicate a need for broader inclusion criteria within families than might traditionally have been considered. This session will also present new methods for investigating pedigrees in the era of whole genome sequencing.