Shared genetic architecture between schizophrenia and subcortical brain volumes implicates early neurodevelopmental processes and brain development in childhood

Abstract

Patients with schizophrenia have consistently shown brain volumetric abnormalities, implicating both etiological and pathological processes. However, the genetic relationship between schizophrenia and brain volumetric abnormalities remains poorly understood. Here, we applied novel statistical genetic approaches (MiXeR and conjunctional false discovery rate analysis) to investigate genetic overlap with mixed effect directions using independent genome-wide association studies of schizophrenia (n=130,644) and brain volumetric phenotypes, including subcortical brain and intracranial volumes (n=33,735). We found brain volumetric phenotypes share substantial genetic variants (74%~96%) with schizophrenia, and observed 107 distinct shared loci with sign consistency in independent samples. Genes mapped by shared loci revealed (1) significant enrichment in neurodevelopmental biological processes, (2) three co-expression clusters with peak expression at the prenatal stage, and(3) genetically imputed thalamic expression of CRHR1 and ARL17A was associated with the thalamic volume as early as in childhood. Together, our findings provide evidence of shared genetic architecture between schizophrenia and brain volumetric phenotypes and suggest altered early neurodevelopmental processes and brain development in childhood may be involved in schizophrenia development.

Schizophrenia, inflammation and temporal change in brain morphology: an omnigenic Mendelian randomization study

“…Interestingly, Weiqiu et al, in their study, identified a ramarkable shared genetic architecture between schizophrenia and subcortical volumes, in particular, 54% for schizophrenia. Furthermore, this study also found that shared genetic loci reached the expression peak at the prenatal age, consistent with our assumption that the pathogenesis of schizophrenia, especially the one involving immunology, could start around the perinatal period, either triggered or precipitated by intrauterine infection or inflammation involving CRP [34].…”

“…Our results imply that the change in the CRP level caused by SCZ leads to a misaligned growth trajectory of WMV between cerebral and cerebellar areas. Our study, for the first time, established the causal link from CRP to the pallidum’s GMV changes which played a substantial role in various mental functions [32, 33]. Interestingly, Weiqiu et al, in their study, identified a ramarkable shared genetic architecture between schizophrenia and subcortical volumes, in particular, 54% for schizophrenia.…”

Shared Genetic Architecture between Parkinson's Disease and Brain Structural Phenotypes

“…We then systematically quantified genetic architecture beyond genome‐wide genetic correlations between PD and BSPs by using MiXeR and discovered a modest genetic overlap between PD and SA, TH, caudate volume, hippocampus volume, nucleus accumbens volume, putamen volume, and thalamus volume, respectively, which showed patterns of mixed effect directions concealed by estimates of genome‐wide genetic correlations. However, the lower degree of overlap between PD and many brain MRI measures, compared with that reported for psychiatric diagnoses, 29,40 could potentially be caused by the intricate interplay between genetic and environmental factors influencing PD. The shared genetic associations were found by conjFDR at individual variant and locus levels, and Q‐Q plots indicated significant polygenic overlap between PD and SA, TH, ICV, hippocampus volume, and putamen volume, respectively.…”

The genetic relationships between brain structure and schizophrenia

“…This locus harbors a inversion polymorphism and includes PLEKHM1, MAPT, KANSL1 and CRHR1. CRHR1 encodes the main receptor of corticotrophin-releasing hormone and has recently been highlighted in a study of shared genetic effects on schizophrenia and subcortical volumes [54]. MAPT encodes microtubule-associated protein tau, which is known for its role in axonal transport and neurite outgrowth and has previously been associated with schizophrenia and structural MRI metrics [7].…”