Elsevier

NeuroImage

Volume 59, Issue 3, 1 February 2012, Pages 2057-2061
NeuroImage

Neuregulin-1 genotype is associated with structural differences in the normal human brain

https://doi.org/10.1016/j.neuroimage.2011.10.007Get rights and content

Abstract

The human neuregulin-1 (NRG-1) gene is highly expressed in the brain, is implicated in numerous functions associated with neuronal development, and is a leading candidate gene for schizophrenia. The T allele of SNP8NRG243177, part of a risk haplotype for schizophrenia, has been previously associated with decreases in white matter in the right anterior internal capsule and the left anterior thalamic radiation. To our knowledge no studies have described the effects of SNP8NRG243177 on grey matter volume at a voxelwise level. We assessed associations between this SNP and brain structure in 79 general population volunteers from the Northern Finland 1966 Birth Cohort (NFBC 1966). We show, for the first time, that genetic variation in SNP8NRG243177 is associated with variation in frontal brain structure in both grey and white matter. T allele carriers showed decreased grey matter volume in several frontal gyri, including inferior, middle and superior frontal gyri and the anterior cingulate gyrus, as well as decreased white matter volume in the regions of the genu and body of the corpus callosum, anterior and superior corona radiata, anterior limb of the internal capsule and external capsule regions traversed by major white matter tracts of the anterior thalamic radiation, and the inferior fronto-occipital fasciculus. These results suggest that this genetic variant may mediate risk for schizophrenia, in part, through its effect on brain structure in these regions.

Introduction

Neuregulin-1 proteins are important for neural development and synaptic plasticity (Mei and Xiong, 2008). NRG-1 is one of the leading candidate genes for schizophrenia (Harrison and Law, 2006, Stefansson et al., 2002), though the mechanism through which risk is conferred is uncertain, especially as the putative schizophrenia risk alleles are noncoding.

Considerable attention has been paid in understanding the role of the NRG-1 polymorphism SNP8NRG243177, as it is associated with risk for schizophrenia both on its own and as part of a haplotype identified by the deCODE consortium (Stefansson et al., 2003), and as evidence from several research lines (clinical observation, neuroimaging, neuropathology) suggest that this is a functional polymorphism (Buonanno, 2010). Specifically, McIntosh and colleagues showed that homozygotes for the SNP8NRG243177 (rs6994992) T allele show decreases in white matter density in the right anterior internal capsule (McIntosh et al., 2008) and, in a partially overlapping sample, the same group showed that T allele carriers also have reduced white matter integrity in the left anterior thalamic radiation (Sprooten et al., 2009). Functional MRI studies showed increases in frontal lobe activation associated with T homozygote status (Hall et al., 2006, Mechelli et al., 2010, Mechelli et al., 2009) suggesting an inefficiency in neural processing. Clinical studies from two independent groups have suggested that, in populations at risk for psychosis, T allele homozygosity predicted subsequent development of psychotic illness (Hall et al., 2006, Keri et al., 2009). Law and colleagues have suggested that SNP8NRG243177 affects NRG-1 transcription rates, as they found that hippocampal mRNA expression of type IV NRG-1 was higher in individuals carrying the T-allele at SNP8NRG243177 (Law et al., 2006). This combination of evidence from clinical, postmortem and neuroimaging studies provides mounting evidence of functional effects of variation at SNP8NRG243177.

While there are a handful of published studies on white matter and SNP8NRG243177, its effect on grey matter volume has received less study. For example, there have been no studies describing the effects of SNP8NRG243177 on grey matter at a voxelwise level in healthy humans, although there have been a few studies assessing the effects of NRG-1 variation (either using different SNPs or haplotypes or studying patients rather than controls) on a priori defined regional grey matter volumes (Addington et al., 2007, Gruber et al., 2008, Winterer et al., 2008). Given that NRG-1 plays a role in synapse development, synaptic plasticity and neuronal survival (Mei and Xiong, 2008), it is highly plausible that genetic variation in NRG-1 genotype will influence grey matter volume, and, if so, this could be a mechanism through which the gene is linked to risk for schizophrenia. We therefore wished to test whether variation at SNP8NRG243177 is associated with variation in grey matter structure in humans. We reasoned that as NRG-1 is expressed widely throughout the brain (Law et al., 2004), it would be important to assess the effect of NRG genotype on grey matter volume at a whole-brain voxelwise level rather than confining our search to a specific brain region. We also wanted to examine whether we could replicate the previously published findings linking T allele status at SNP8NRG243177 to impaired white matter structures traversed by the anterior thalamic radiation.

Section snippets

Materials and methods

Subjects: The Northern Finland 1966 Birth Cohort (NFBC 1966) is an unselected, general population birth cohort ascertained during midpregnancy (n = 12,068), representing 96% of the live born children in Lapland and Oulu provinces with an expected delivery date during 1966 (Rantakallio, 1969). Between 1999 and 2001, (age 33–35 years), MRI data were collected on 104 non-psychotic cohort members randomly sampled from the Oulu region. Sampling was randomised in a gender-stratified manner, as one

Results

After correcting for sex, there was no significant difference in mean total intracranial volume (C/C = 1479.49 mL ± 149.82, T carriers = 1491.79 mL ± 107.7), mean total grey matter (C/C = 649.21 mL ± 57.72, T carriers = 652.3 mL ± 47.77), or mean total white matter (C/C = 582.47 mL ± 69.82, T carriers = 578.47 mL ± 23.29) between the genotypes as measured from the tissue segmented maps in native space. There was no significant difference in mean proxy IQ (C/C = 99.90 ± 10.47, T carriers = 99.35 ± 11.41),

We compared the brain

Discussion

We show, that a genetic variation at SNP8NRG243177 on NRG-1 is associated with normal variation in human brain structure in both frontal grey and white matter. We show that the risk SNP8NRG243177 T allele carriers have decreased grey matter volume in several frontal gyri, including inferior, middle and superior frontal gyri and the anterior cingulate gyrus. In addition, T allele carriers have decreased white matter volume in the regions of the genu and body of the corpus callosum, anterior and

Conclusion

We show, for the first time, that a variation at SNP8NRG243177, in the candidate schizophrenia risk gene NRG-1 is associated with both frontal grey matter and white matter structure in general population volunteers. The congruence of the brain regions in which we find NRG-1 associations and regions implicated as abnormal in schizophrenia is consistent with the theory that this genetic variant may mediate risk for schizophrenia at least in part through its effect on brain structure.

Acknowledgments

This work was supported by awards from NARSAD: The Brain and Behavior Research Fund (to AB, MI, JM and GKM), the Medical Research Council (to GKM), the Sigrid Juselius Foundation (to AB, MI), Academy of Finland (to MI, JV and JM), and Isaac Newton Trust (to AB, KR and PBJ), EB is employed 50% by GlaxoSmithKline and 50% by the University of Cambridge.

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