Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder

Area of Science:

• Psychiatric Genetics
• Neuroscience
• Genomics

Background:

• Schizophrenia and bipolar disorder are heritable psychiatric conditions with shared genetic factors.
• Identifying specific genetic variants is crucial for understanding disease mechanisms.

Purpose of the Study:

• To conduct a genome-wide association study (GWAS) in an ethnically homogeneous population to identify novel genetic risk factors for schizophrenia.
• To validate findings in replication cohorts and explore the functional implications of identified variants.

Main Methods:

• Genome-wide association study (GWAS) of 904 schizophrenia cases and 1,640 controls from the Ashkenazi Jewish population.
• Replication and extension across 11 cohorts (23,191 samples) for multiple ethnicities.
• Analysis of single-nucleotide polymorphism (SNP) association with gene expression (NDST3) in postmortem cerebellum.

Main Results:

• Identification of a novel genome-wide significant risk locus at chromosome 4q26.
• The top SNP (rs11098403) showed consistent association with schizophrenia and bipolar disorder across diverse populations (Pmeta=9.49 × 10⁻¹²).
• This SNP significantly predicted postmortem cerebellar expression of NDST3, an enzyme involved in heparan sulfate metabolism.

Conclusions:

• The study highlights the utility of founder populations for genetic discovery in psychiatric disorders.
• The identified locus and its association with NDST3 suggest a role for heparan sulfate metabolism in the pathophysiology of schizophrenia and bipolar disorder.
• Heparan sulfate's role in neurite outgrowth and synaptic function may be critical in these conditions.