Taking advantage of an opportunity to explore the effects of multiple genetic variations on specific brain systems.
The Emerging Opportunity of Brain Genomics
Psychiatric illness arises from interplay between genes and the environment. Schizophrenia, bipolar disorder, anxiety disorder, and autism are all associated with high familial risk and estimates of heritability. Risk for autism, in particular, is raised by a factor of 25 to 50 in people with affected first-degree relatives. The risks of bipolar disorder and schizophrenia are raised tenfold. Thus, identification of genetic risk factors and understanding the link between heredity and psychiatric illness are of paramount interest.
Within this context, a significant challenge for psychiatric research is the complexity of the process through which genes exert their influence on cognition. There is no expectation of a one-to-one correspondence between genes and phenotype, and there are documented examples of multiple psychiatric symptoms arising from the alterations to the same genes. For example, sequence variations in the well-studied “Disrupted In Schizophrenia” (DISC) genes are also associated with bipolar disorder, manic depression, and autism. The ability to directly visualize the effects of genetic variation on neural systems is a central motivation for emphasis on brain genomics.
Specifically, there are several major opportunities for neuroimaging methods in genomics research. First, brain genomics provide an assay for exploring the effects of reported genetic variations on the brain. That is, given the large numbers of association-based and biologically-motivated genetic targets, the field desperately needs methods to rapidly identify which genetic variations influence the brain in biologically meaningful ways. Second, behavioral phenotyping and clinical diagnosis, while providing the basis for research classification to date, are unlikely to be sufficient for the next era of progress. The lesson of DISC gene variations as well as the presence of shared symptoms across disorders suggests that there may be convergent underlying processes at work. Neuroimaging methods provide an opportunity to make more refined phenotypic measurements as well as break down barriers across traditional disease classification schemes.
Perhaps most critically, neuroimaging provides an opportunity to explore the effects of multiple genetic variations on specific brain systems. Convergent studies reported in 2008 of rare, highly penetrant genetic mutations by MGH scientists revealed that insertions and deletions on diverse genes can produce similar psychiatric illness.
The lesson learned from these groundbreaking studies is that alterations to numerous genes can disrupt similar functions. That is, answers to the question of how genes influence risk for psychiatric illness may not lie in any single gene or even a small number of genes. Rather, molecular pathways may have numerous vulnerabilities that stem from the many ways their protein or regulatory building blocks can be altered. Common genetic variations that each make small contributions to brain function, such as those linked to frequently occurring single nucleotide polymorphisms (SNPs) and sequence repeats, may follow similar principles. Illness may arise from the combined effects of many small influences of distinct genomic loci within the same person – what Harvard Provost Steven Hyman referred to as the “common disease-common variant hypothesis” in his 2008 tutorial in Nature.
On the one hand, such complexity is daunting, and the path from where we are now to where we need to go to unravel mechanisms underlying psychiatric illness is long. On the other hand, there are clear paths forward to which psychiatric neuroimaging will make major contributions and short-term milestones that can have direct influence on clinical care. Specifically, brain structural and functional phenotypes can be used to explore the cumulative affects of genetic variations. For example, by measuring functional activity in prefrontal circuits, a recent report demonstrated that abnormal dopamine signaling in the prefrontal cortex was influenced by two distinct common genetic variations – one that affects the availability of dopamine (COMT) and a second that regulates COMT through upstream influences (MTHFR). A direct implication of this work is that treatment regimes might be tailored for individuals based on which variants of COMT and MTHFR protein products they express.
The MGH Department of Psychiatry is leading a research effort that merges psychiatric genetics and neuroimaging. The Harvard community has tremendous strength in genomics, and particularly in psychiatric genetics as embodied within the Psychiatric Genetics Program in Mood and Anxiety Disorders, and the Psychiatric and Neurodevelopmental Genetics Unit. Investigators within the psychiatric research program have taken active roles in large-scale and multi-site neuroimaging studies that explore links between genetic variation and differences in neural systems.