Do Gene Variants Affect Gray Matter Volume in Schizophrenia?

DNA structure, gene, DNA
DNA (deoxyribonucleic acid) structure, illustration.
Researchers discovered that the mechanism of the gene SLC39A8 that is associated with schizophrenia can be manipulated with pharmacology, which has yet to be developed.

The single-nucleotide polymorphism rs13107325 was found to be associated with gray matter volume in the putamen. This association is weakened in both patients with schizophrenia and their unaffected siblings, according to a study published in JAMA Psychiatry. Researchers analyzed brain images and genetic sequencing of patients with schizophrenia, their unaffected siblings, and healthy controls to determine gray matter volume at the putamen, genetic variants, and changes that occur across a life-span.

Data for the Voxelwise genome-wide association study had 4 arms: a discovery arm with data coming from the IMAGEN baseline records of healthy adolescents; a longitudinal arm with data coming from the IMAGEN follow-up records of healthy adults; a replication arm from healthy controls looking at life-span changes with data coming from the Saguenay Youth Study, Three-City Study, the Lieber Institute for Brain Development sample, and UK Biobank; and a clinical arm looking at patients with schizophrenia and unaffected siblings from the Lieber Institute for Brain Development sample. Data collection included

  • genotyped blood samples,
  • magnetic resonance imaging of brain structures, and
  • identifications of gene mutations using the UK Brain Expression Consortium database.

The study included 1721 healthy adolescents, 8690 healthy participants, 157 patients with schizophrenia, and 149 unaffected siblings. Analyzing the discovery arm, researchers found an association between the single-nucleotide polymorphism rs13107325 and larger volume in bilateral putamen and the single-nucleotide polymorphism rs7182018 and greater gray matter volumes of 2 clusters in bilateral central sulcus.

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Analyzing the replication arm, researchers found a positive association of single-nucleotide polymorphism rs13107325 in the left putamen in the Saguenay Youth Study and a positive association of rs13107325 with gray matter volumes of the putamen clusters in the UK Biobank sample. According to the UK Brain Expression Consortium, the single-nucleotide polymorphism rs13107325 showed lower expression of SLC39A8 (t₁₂₇=-3.87, 95% CI, -6.51 to -1.73, P =.0002), and according to this study, specifically in the putamen (P <.0008).

Analyzing the clinical arm, researchers found that in both patients with schizophrenia and unaffected siblings, the association of rs13107325 and volume in the right putamen was insignificant. Compared with healthy participants, patients with schizophrenia had a significantly weakened association between rs13107325 and volume at the putamen (z=-3.05; P =.002), as well as unaffected siblings (z=-2.08; P =.04). Limitations of this study include a conservative strategy, which could give false-negatives due to sample size in the discovery arm, and the lack of evidence proving rs7182018 is involved in the pathology of schizophrenia or associated with the expression of SLC39A8.

The researchers concluded that the results “identified a gene that points to a potential new mechanism associated with both ion transporter and immune reaction for development of psychopathology, in particular associated with schizophrenia” and provided “a target for preemptive developmental interventions aimed at restoring the functional effect of this mutation.”

Six authors declared multiple associations with pharmaceutical companies. Please refer to the original reference for a complete list of authors’ disclosures.


Luo Q, Chen Q, Wang W, et al. Association of a schizophrenia-risk nonsynonymous variant with putamen volume in adolescents: A voxelwise and genome-wide association study [published online January 16, 2019]. JAMA Psychiatry. doi: 10.1001/jamapsychiatry.2018.4126