Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia

P H Lee, J T Baker, A J Holmes, N Jahanshad, T Ge, J-Y Jung, Y Cruz, D S Manoach, D P Hibar, J Faskowitz, K L McMahon, G I de Zubicaray, N H Martin, M J Wright, D Öngür, R Buckner, J Roffman, P M Thompson, J W Smoller

Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide single-nucleotide polymorphism (SNP) and neuroimaging data from 1750 healthy individuals. We find that schizophrenia-associated genetic variants explain a significantly enriched proportion of trait heritability in eight brain phenotypes (false discovery rate=10%). In particular, intracranial volume and left superior frontal gyrus thickness exhibit significant and robust associations with schizophrenia genetic risk under varying SNP selection conditions. Cross-disorder comparison suggests that the neurogenetic architecture of schizophrenia-associated brain regions is, at least in part, shared with other psychiatric disorders. Our study highlights key neuroanatomical correlates of schizophrenia genetic risk in the general population. These may provide fundamental insights into the complex pathophysiology of the illness, and a potential link to neurocognitive deficits shaping the disorder.Molecular Psychiatry advance online publication, 11 October 2016; doi:10.1038/mp.2016.164.