Neuregulin-1 genotype is associated with structural differences in the normal human brain
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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2020, Behavioural Brain ResearchCitation Excerpt :Genetics may also have an effect on ALIC structure and its psychiatric sequelae. Variations in NRG1 and ErbB4, which are associated with both bipolar disorder and schizophrenia, as well as certain polymorphisms in ANK3, a known risk factor for bipolar disorder, are associated with reduced ALIC density, volume, and FA [176–180]. Although BD is clinically distinct from MDD, macro- and micro- architectural changes in the ALIC, as well as variations in ALIC FA with the genetic variations implicated in BD, suggest possible overlap in the underlying neuronal circuitry [181].
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2015, Neurology Psychiatry and Brain ResearchCitation Excerpt :The carriers of the risk T allele (n = 46) of neuregulin variant SNP8NRG243177 (rs6994992) were shown to have decreased WM density in the right anterior internal capsule (peak 1: MNI coordinates = (29, 30, 7), t = 4.41, Pcorrected < 0.028; peak 2: MNI coordinates = (29, 26, 8), t = 4.38, Pcorrected < 0.016; peak 3: MNI coordinates = (29, 23, 12), t = 4.26, Pcorrected < 0.023)139; reduced WM integrity (n = 30) in the left anterior thalamic radiation (P < 0.001);140 decreased GMV (n = 41) in several frontal gyri (P < 0.003) and decreased WMV in the regions of the genu and body of the corpus callosum, anterior and superior corona radiata, anterior limb of the internal capsule and the external capsule regions, traversed by major WM tracts of the anterior thalamic radiation and the inferior fronto-occipital fasciculus (P < 0.004).127 The findings from the above two independent studies by Barnes et al.127 and Sprooten et al.140 also clearly demonstrate the significant impact of NRG1 polymorphism rs6994992 on anterior thalamic radiation, where the polymorphism rs6994992 was shown to be associated with reduced WMV/white matter integrity in anterior thalamic radiation in healthy subjects. (ii).
An exploratory association study of the influence of dysbindin and neuregulin polymorphisms on brain morphometry in patients with schizophrenia and healthy subjects from South India
2014, Asian Journal of PsychiatryCitation Excerpt :Even though the NRG1 polymorphism rs35753505 has been reported to be a core marker of schizophrenia (Kukshal et al., 2013; Nawaz et al., 2013; Prata et al., 2009), there have surprisingly been no previous studies that have looked at brain morphometric changes associated with this polymorphism in healthy or schizophrenia subjects. Previous studies have reported decreased regional brain volumes associated with the rs6994992 polymorphism (Barnes et al., 2012; McIntosh et al., 2008). Therefore ours is the initial report of a trend toward increased regional brain volumes associated with the rs35753505 polymorphism.
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These authors contributed equally to this work.