Prenatal expression patterns of genes associated with neuropsychiatric disorders

Abstract

Objective: Neurodevelopmental disorders presumably involve events that occur during brain development. The authors hypothesized that neuropsychiatric disorders considered to be developmental in etiology are associated with susceptibility genes that are relatively upregulated during fetal life (i.e., differentially expressed).

Method: The authors investigated the presence of prenatal expression enrichment of susceptibility genes systematically, as composite gene sets associated with six neuropsychiatric disorders in the microarray-based "BrainCloud" dorsolateral prefrontal cortex transcriptome.

Results: Using a fetal/postnatal log2-fold change threshold of 0.5, genes associated with syndromic neurodevelopmental disorders (N=31 genes, p=3.37×10-3), intellectual disability (N=88 genes, p=5.53×10-3), and autism spectrum disorder (N=242 genes, p=3.45×10-4) were relatively enriched in prenatal transcript abundance, compared with the overall transcriptome. Genes associated with schizophrenia by genome-wide association studies were not preferentially fetally expressed (N=106 genes, p=0.46), nor were genes associated with schizophrenia by exome sequencing (N=212 genes, p=0.21), but specific genes within copy-number variant regions associated with schizophrenia were relatively enriched in prenatal transcript abundance, and genes associated with schizophrenia by meta-analysis were functionally enriched for some neurodevelopmental processes. In contrast, genes associated with neurodegenerative disorders were significantly underexpressed during fetal life (N=46 genes, p=1.67×10-3).

Conclusions: The authors found evidence for relative prenatal enrichment of putative susceptibility genes for syndromic neurodevelopmental disorders, intellectual disability, and autism spectrum disorder. Future transcriptome-level association studies should evaluate regions other than the dorsolateral prefrontal cortex, at other time points, and incorporate further RNA sequencing analyses.

Figure 1. Fetal Effect, by individual gene

Fetal Effect is Pre vs Post Natal Log2 (Fold Change), or Regression Coefficient n = 269 controls (including 38 fetal samples)

Figure 2. Density Plot of Fetal Effect by Gene Set and Wilcoxon signed-rank test

The density of each gene set’s fetal effect compared to the fetal effect of the whole genome. The x-axis is the fetal effect, or regression coefficient (pre-natal vs post-natal) and y-axis is the density. Black line indicates the genome and colored line indicates the gene set. Red line indicates significant increase, Purple line indicates significant decrease. Blue line is default, no significant difference in fetal effect of gene set compared to the transcriptome. One-sided p-values are shown for Wilcoxon signed-rank test for each gene set, elevation in the positive direction on the upper right side, and decrease in the negative direction on the upper left side.