Research using a combination of genome-wide association studies and functional magnetic resonance imaging (fMRI) has lead to an outpouring of genetic variants related to specific diseases and their association with specific differences in brain anatomy and functional connectivity. One of the striking realizations from this work is that the genetic variants and the associated differences in brain anatomy and functional connectivity are found in the general population, in people who are apparently healthy both physically and psychologically.

The brief paper “Neural Mechanisms of a Genome-Wide Supported Psychosis Variant” published May 1, 2009 in Science describes functional brain connections specific to a genetic variant (technically a single-nucleotide polymorphism or SNP pronounced “snip”) known as rs1344706 in the ZNF804A gene. This particular version of the gene (the risk allele) is associated with schizophrenia and bipolar disorder.

The research team imaged the brains of 115 genotyped healthy people without diagnosis of schizophrenia or bipolar disorder. The results showed that those carrying the risk allele have reduced functional connectivity within the dorsolateral prefrontal cortex and increased functional connections between the dorsolateral prefrontal cortex and the hippocampal formation. These findings are consistent with the disturbed executive function of the dorsolateral prefrontal cortex in those with schizophrenia.

The results also showed that those carrying the risk allele have extensive increases in functional connections between the amygdala and various other brain areas including the hippocampus, orbitofrontal cortex, and medial prefrontal cortex. These findings are consistent with emotional instability observed in those diagnosed with bipolar disorder.

How a risk allele interacts with other alleles, environmental factors, or other unknown factors to result in the emergence of a disease like schizophrenia or bipolar disorder remains a mystery. Why are healthy people able to carry a risk allele without any apparent ill effects? Why do some people with the same risk allele have schizophrenia but others have bipolar disorder? We don’t know but we seem to be on track for discovering some of the answers in the not too distant future.


Other related blog posts:

Autism or Autism Trait in the Normal Population? The Crisis of Defining Normal

Genetics of Autism: Challenging Psychiatric Classifications