Basic helix-loop-helix transcription factor NEUROG1 and schizophrenia: effects on illness susceptibility, MRI brain morphometry and cognitive abilities.

Transcription factors, including the basic helix-loop-helix (bHLH) family, regulate numerous genes and play vital roles in controlling gene expression. Consequently, transcription factor mutations can lead to phenotypic pleiotropy, and may be a candidate mechanism underlying the complex genetics and heterogeneous phenotype of schizophrenia. Neurogenin1 (NEUROG1; a.k.a. Ngn1 or Neurod3), a bHLH transcription factor encoded on a known schizophrenia linkage region in 5q31.1, induces glutamatergic and suppresses GABAergic neuronal differentiation during embryonic neurodevelopment. The goal of this study is to investigate NEUROG1 effects on schizophrenia risk and on phenotypic features of schizophrenia. We tested 392 patients with schizophrenia or schizoaffective disorder and 226 healthy normal volunteers for association with NEUROG1. Major alleles on two NEUROG1-associated SNPs (rs2344484-C-allele and rs8192558-G-allele) were significantly more prevalent among patients (p<or=.0018). Approximately 80% of the sample also underwent high-resolution, multi-spectral magnetic resonance brain imaging and standardized neuropsychological assessment. There were significant rs2344484 genotype main effects on total cerebral gray matter (GM) and temporal GM volumes (p<or=.05). C-allele-carrier patients and healthy volunteers had smaller total cerebral GM and temporal GM volumes than their respective T-homozygous counterparts. rs2344484-C-allele was further associated with generalized cognitive deficits among schizophrenia patients but not in healthy volunteers. Our findings replicate previous association between NEUROG1 and schizophrenia. More importantly, this is the first study to examine brain morphological and neurocognitive correlates of NEUROG1. rs2344484-C-allele may affect NEUROG1's role in transcription regulation such that brain morphology and cognitive abilities are altered resulting in increased susceptibility to develop schizophrenia.