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. 2013:4:2739.
doi: 10.1038/ncomms3739.

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

Todd Lencz  1 , Saurav Guha, Chunyu Liu, Jeffrey Rosenfeld, Semanti Mukherjee, Pamela DeRosse, Majnu John, Lijun Cheng, Chunling Zhang, Judith A Badner, Masashi Ikeda, Nakao Iwata, Sven Cichon, Marcella Rietschel, Markus M Nöthen, A T A Cheng, Colin Hodgkinson, Qiaoping Yuan, John M Kane, Annette T Lee, Anne Pisanté, Peter K Gregersen, Itsik Pe'er, Anil K Malhotra, David Goldman, Ariel Darvasi
Affiliations

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

Todd Lencz et al. Nat Commun. 2013.

Abstract

Schizophrenia and bipolar disorder are major psychiatric disorders with high heritability and overlapping genetic variance. Here we perform a genome-wide association study in an ethnically homogeneous cohort of 904 schizophrenia cases and 1,640 controls drawn from the Ashkenazi Jewish population. We identify a novel genome-wide significant risk locus at chromosome 4q26, demonstrating the potential advantages of this founder population for gene discovery. The top single-nucleotide polymorphism (SNP; rs11098403) demonstrates consistent effects across 11 replication and extension cohorts, totalling 23, 191 samples across multiple ethnicities, regardless of diagnosis (schizophrenia or bipolar disorder), resulting in Pmeta=9.49 × 10(-12) (odds ratio (OR)=1.13, 95% confidence interval (CI): 1.08-1.17) across both disorders and Pmeta=2.67 × 10(-8) (OR=1.15, 95% CI: 1.08-1.21) for schizophrenia alone. In addition, this intergenic SNP significantly predicts postmortem cerebellar gene expression of NDST3, which encodes an enzyme critical to heparan sulphate metabolism. Heparan sulphate binding is critical to neurite outgrowth, axon formation and synaptic processes thought to be aberrant in these disorders.

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Figures

Figure 1
Figure 1. Manhattan plot demonstrating genome-wide association results.
Logistic regression (additive model) was used to test the association between genetic variants and schizophrenia in the Ashkenazi Jewish discovery cohort.
Figure 2
Figure 2. Q–Q plot of the genome-wide association results.
Logistic regression (additive model) was used to test the association between genetic variants and schizophrenia in the Ashkenazi Jewish discovery cohort.
Figure 3
Figure 3. Regional association plot of the 4q26 region in the discovery cohort after HapMap3 imputation.
Note that no imputed SNP has a lower P-value (based on logistic regression under the additive model) than rs11098403.
Figure 4
Figure 4. Odds ratio plot showing allelic effects of the G allele of rs11098403 in the discovery and 10 independent cohorts of schizophrenia or bipolar disorder cases and controls.
P-values were generated using logistic regression under the additive model and are presented in parentheses. Error bars represent the 95% confidence interval of the odds ratios.
Figure 5
Figure 5. Expression of NDST3 in postmortem cerebellar tissue as a function of genotype.
Associations within the LD block containing rs11098403 were tested using logistic regression under the additive model. Three plots are presented on the same scale for these eQTL analyses. The raw (unconditioned) P-values are shown in blue, the P-values conditioned on rs11098403 (hg18 coordinates) are shown in green and the P-values separately conditioned on rs17862991 are shown in red.
Figure 6
Figure 6. In silico analysis of region immediately surrounding top GWAS SNP rs11098403.
An H3K4me1 activation mark at this locus is observed in H1 human embryonic cell lines (grey arrow). A close proxy SNP (rs17862077, which is 2,953 bp telomeric to rs11098403; r2=0.96 in 1,000 Genomes CEU), neighbours an unmethylated CpG island (red arrow), which is the only such site within an 850-kb intergenic window. Additional SNPs with the same LD relationship to rs11098403 (for example, rs11562906) localize to an H3K4me1 mark detected in hippocampus (blue arrow).
Figure 7
Figure 7. RNA-seq expression profile in hippocampus of rat, macaque and human.
Genomic features in the syntenic region of 1 Mb around human rs11098403 are represented. TATA boxes were predicted by TSSG (Softberry Inc) and the predicted TATA box locations were depicted with vertical arrows (red on plus strand and blue on minus strand of chromosome 4). In cross-species genomic sequence alignment, high sequence similarity was depicted in red (same orientation) and blue (opposite orientation); low sequence similarity was depicted in cyan. Green arrowed lines represent the location and orientation of the repeat sequences around rs11098403; the green horizontal arrow in the bottom panel corresponds to the left-most green arrow in the panel above.
Figure 8
Figure 8. Comparison of novel hippocampal transcript expression detected by RNA-seq.
Expression data were observed in publicly available UCSC browser tracks. There is some overlap with small transcripts observed in prior studies of brain, but not other tissues.
Figure 9
Figure 9. BLAT alignment of DNA sequences underlying the novel transcript.
The novel transcript (observed in Fig. 7) sequence demonstrates considerable homology (red) to an included intron variant (light blue) of NDST3.
See this image and copyright information in PMC

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