This website will ultimately provide a comprehensive workflow for functional genomic analyses with relevance neuropsychiatric disease. The goal is to identify the biological & molecular pathways that contribute to highly heritable disorders, such as schizophrenia or autism spectrum disroders (ASD). The general principles were outlined in two recent reviews:
- Gandal MJ., et al. "The road to precision psychiatry: translating genetics into disease mechanisms" Nature Neuroscience 19, 1397–1407 (2016) doi:10.1038/nn.4409 and
- Parikshak NN, Gandal MJ, and Geschwind "Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders" Nature Reviews Genetics 16, 441–458 (2015) doi:10.1038/nrg3934.
Two fundamental approaches can be taken when trying to unravel the genetic underpinning of psychiatric disorders. The classic "Forward Genetic Approach" can be used to understand the contribution & biological impact of a single disease-associated genetic variant or locus.
Forward Genetic Approach
This is the simplest, most reductionistic approach, with the greatest ease of interpretation. However, most neuropsychiatric disorders have a highly complex, polygenic, and pleiotropic genetic architecture. This means that there will likely be 1000s of genetic variants contributing to each psychiatric disorder, many of which are common in the population and none of which will be fully penetrant for disease (or even close). Indeed, the most strongly associated common variants with disorders like schizophrenia have odds-ratios on the order of 1.2, increasing disease risk by 20%. This represents an absolute disease risk of 1.2% (i.e., still very small), assuming a ~1% population prevalance of schizophrenia. Further complicating this picture, the majority of risk variants identified to date for psychiatric disorders lie in non-protein-coding regions of the genome. As such, the immediate biological impact of such genetic variation is unclear. Variants within protein-coding regions can act to alter the amino acid structure of a protein, potentially disrupting biochemical function. However, non-coding variants are much more difficult to interpret, as they may influence the expression or splicing of target genes at a substantial distance.
Reverse Genetic Approach
The reverse genetic approach can help to identify potential common, downstream pathways that are disrupted in a particular disorder by the additive (or interactive) effects of multiple (usually unknown) genetic or environmental risk factors. The assumption here is that common disorders, like ASD or schizophrenia,