Genes implicated by a methylome-wide schizophrenia study in neonatal blood show differential expression in adult brain samples.

Schizophrenia is a disabling disorder involving genetic predisposition in combination with environmental influences that likely act via dynamic alterations of the epigenome and the transcriptome but its detailed pathophysiology is largely unknown. We performed cell-type specific methylome-wide association study of neonatal blood (N = 333) from individuals who later in life developed schizophrenia and controls. Suggestively significant associations (P < 1.0 × 10-6 ) were detected in all cell-types and in whole blood with methylome-wide significant associations in monocytes (P = 2.85 × 10-9 -4.87 × 10-9 ), natural killer cells (P = 1.72 × 10-9 -7.82 × 10-9 ) and B cells (P = 3.8 × 10-9 ). Validation of methylation findings in post-mortem brains (N = 596) from independent schizophrenia cases and controls showed significant enrichment of transcriptional differences (enrichment ratio = 1.98-3.23, P = 2.3 × 10-3 -1.0 × 10-5 ), with specific highly significant differential expression for, for example, BDNF (t = -6.11, P = 1.90 × 10-9 ). In addition, expression difference in brain significantly predicted schizophrenia (multiple correlation = 0.15-0.22, P = 3.6 × 10-4 -4.5 × 10-8 ). In summary, using a unique design combining pre-disease onset (neonatal) blood methylomic data and post-disease onset (post-mortem) brain transcriptional data, we have identified genes of likely functional relevance that are associated with schizophrenia susceptibility, rather than confounding disease associated artifacts. The identified loci may be of clinical value as a methylation-based biomarker for early detection of increased schizophrenia susceptibility.