Searching for the Mechanisms of Psychosis in Genes and Adversities Mediating Inflammation: Clues from Paternal Age Related Mutations

Those studying the origins of schizophrenia were historically separated into hereditarian versus psychosocial causation camps. Nonetheless, advances in neuroscience and the genomic revolution were expected to unravel its genetic underpinnings and light the way to novel strategies for preventing and treating severe mental illness. That has not transpired, and the high heritability driving genetic research remained unexplained until it was reconsidered in light of influential, family-wise rare variants. These are predominantly point mutations that continually enter the population in association with advancing paternal age and leave the population if they impair fecundity, as in schizophrenia. Neither of the historical camps, those holding that psychosis is predominantly genetic, nor those focused on environmental causation, initially welcomed the paternal-age-related mutation hypothesis. The de novo mutations that cause affected clones of spermatogonia to expand and become over-represented in proportion to paternal age act in proliferative pathways and many also influence immune function and development in offspring. Prenatal adversity, especially maternal commune activation, as well as life-course, and intergenerational exposures may converge with rare and common proinflammatory gene variants to activate the immune system in a mechanistic inflammatory model for schizophrenia. Many other common genes for a disorder likely identify variants that are vulnerable to unrestrained inflammation. Of the many biomarkers proposed, our work focuses on hippocampal inflammatory profiles and vagal hypofunction, which show associations with the microbiome-gut-brain axis. This work suggests opportunities for preventive and therapeutic benefits through anti-inflammatory pathways. Reducing the social and environmental adversity related to inflammation through education and policy change may yield a greater population-wide impact than the valuation of specific risk alleles.