A Common Variant in ERBB4 Regulates GABA Concentrations in Human Cerebrospinal Fluid

The neuregulin 1 (NRG1) receptor ErbB4 is involved in the development of cortical inhibitory GABAergic circuits and NRG1-ErbB4 signaling has been implicated in schizophrenia (SCZ). A magnetic resonance spectroscopy (1H-MRS) study has demonstrated that a single-nucleotide polymorphism in ERBB4, rs7598440, influences human cortical GABA concentrations. Other work has highlighted the significant impact of this genetic variant on expression of ERBB4 in the hippocampus and dorsolateral prefrontal cortex in human post mortem tissue. Our aim was to examine the association of rs7598440 with cerebrospinal fluid (CSF) GABA levels in healthy volunteers (n=155). We detected a significant dose-dependent association of the rs7598440 genotype with CSF GABA levels (G-allele standardized β=−0.23; 95% CIs: −0.39 to −0.07; P=0.0066). GABA concentrations were highest in A homozygous, intermediate in heterozygous, and lowest in G homozygous subjects. When excluding subjects on psychotropic medication (three subjects using antidepressants), the results did not change (G-allele standardized β=−0.23; 95% CIs: −0.40 to −0.07; P=0.0051). The explained variance in CSF GABA by rs7598440 in our model is 5.2% (P=0.004). The directionality of our findings agrees with the aforementioned 1H-MRS and gene expression studies. Our observation therefore strengthens the evidence that the A-allele of rs7598440 in ERBB4 is associated with increased GABA concentrations in the human central nervous system (CNS). To our knowledge, our finding constitutes the first confirmation that CSF can be used to study genotype–phenotype correlations of GABA levels in the CNS. Such quantitative genetic analyses may be extrapolated to other CSF constituents relevant to SCZ in future studies.