Supplement for Bipolar disorder whole genome scan
Sklar et al.
Whole-genome Association Study of Bipolar Disorder
Sklar et al.
Supplementary Table, Figures and Figure Legends
SUPPLEMENTARY TABLES (.xls files):
Table S1. Clinical features of the genome scan samples
Table S2. Evaluation of Hardy-Weinberg equilibrium and missing data
Table S3. Association results for top 200 SNPs in combined sample
Table S4. Multimarker results
Table S5. Comparison of STEP-BD and UCL
Table S7. Comparison of study with WTCCC
Table S6. Replication in NIMH and Edinburgh samples
SUPPLEMENTARY FIGURES (.tif files):
Figure S1. Multidimensional scaling plot of samples
Figure S2. Genome-wide nominal p values for all chromosomes
Figure S3. Quantile-quantile plot of the association results in the combined
STEP-BD and UCL samples
Figure S4. TSPAN8 proxy tests
Figure S5. Plot of top regions of association
Figure S6. Comparison of this study and WTCCC in region of rs4979416
Figure S7. Conditional analyses of DFNB31 region
SUPPLEMENTARY FIGURE LEGENDS
Figure S1. Multidimensional Scaling plot.
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Supplement for Bipolar disorder whole genome scan
Sklar et al.
These plots represent the values of the first two dimensions from a classical
multidimensional scaling analysis based on pairwise identity-by-state distances, for the
final dataset (n=3,469). The top four plots show the entire sample in gray, with either the
US or UK cases or controls highlighted. The bottom two plots show the results of a
similar analysis but with the HapMap samples (left plot: all HapMap founders including
Japanese from Tokyo and Han Chinese (JPT/CHB) and Yoruba from Nigeria (YRI)
individuals as well as CEU individuals; right plot: the CEU individuals and the current
sample). As described in the text, these plots suggest comparability of cases and
controls within US and UK samples.
Figure S2. Genomewide-nominal P values for all chromosomes.
Association results (-log P value) for 372193 SNPs in the combined STEP-BD and UCL
sample are plotted in chromosomal order.
Figure S3. Quantile-Quantile plot of the association results in the combined STEP-BD
and UCL sample.
Observed association results (blue open circles, -log P value) are plotted for 372,193
SNPs against the expected distribution under the null hypothesis of no association
(gray). The upper and lower boundaries of the 95% confidence bands are represented
by the red lines (60).
Figure S4. TSPAN8 Proxy tests.
This figure displays the proxy association report for rs1705236, the second most
associated SNP in the combined STEP-BD and UCL sample, which is in the gene
TSPAN8. Panel A shows the minor allele frequency (MAF), genotyping rate (GENO,
missingness), kilobase distance from rs1705236 (KB), linkage disequilibrium to
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Supplement for Bipolar disorder whole genome scan
Sklar et al.
rs1705236 (RSQ, unit r2), odds ratio (OR), chi-squared statistic (CHISQ) and p-value (P)
for association with disease, tested within a haplotypic context (i.e. contrasting
frequencies of groups of haplotypes, thereby filling in missing genotype data for
rs1705236). Panel B shows the haplotype frequencies for the haplotypes formed from
rs1705236 and 6 flanking SNPs either side, as well as their association with disease.
Finally, panel C is a partial list of the sub-haplotypes from the full set that are in strong
linkage disequilibrium with rs1705236 (RSQ) and associated with disease (OR, CHISQ,
P, as above). In this way, we see that although no markers nearby rs1705236 show
association with disease, this is because they are not themselves in LD with rs1705236.
However, haplotypes formed from these same markers do show strong LD with
rs1705236, and also show a strong association with disease. This would markedly
decrease the chance that this association was spuriously due to genotyping artifact of a
single bad SNP (rs1705236).
Figure S5. Plots of regions of top associations to bipolar disorder
Association results (-logP) are plotted for all SNPs in each gene region passing QC in
the combined STEP-BD and UCL sample. Chromosome position is plotted with
reference to the NCBI build 35 and gene names are plotted with reference to the
University of California at Santa Cruz Genome Browser. Recombination rate as
estimated from the HapMap is plotted in light blue. Blue diamond: SNP with strongest
evidence for association. Red diamonds: strength of LD with blue diamond SNP (darker
red indicates stronger LD).
Figure S6. Comparison of this study and WTCCC in chromosome 9 region of rs4979416
Plot of association tests (negative log p value via logistic regression) for 122 SNPs
centered around rs4979416 for the combined STEP-BD and UCL samples (top panel)
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Supplement for Bipolar disorder whole genome scan
Sklar et al.
and WTCCC (bottom panel). The SNP associated in Baum et al. (rs942518) is indicated
by the red asterisk.
Figure S7. Conditional analysis of chromosome 9 region region of rs4979416
Plots for single SNP association controlling for a particular SNP in the combined STEPBD and UCL samples: a) top panel, rs1490744 (associated upstream of DFNB31), b)
middle panel, rs4979416 (associated in DFNB31) and c) bottom panel, rs16931058
(associated downstream of DFNB31). The original tests are shown in light blue; the red
line shows the conditional test statistic for that SNP. If the signal is independent from the
conditioning SNP, we would expect the red and blue lines to be the same; if the red line
is lower than the blue line, it would suggest that the conditioning SNP could explain that
particular association. The pattern of results suggests that the association at rs1490744
is independent of the association represented by rs4979416 and rs16931058. In
contrast, controlling for association at rs16931058 largely explains the association at
rs4979416, whereas controlling for association at rs4979416 only partially attenuates the
signal at rs16931058. We also performed the analysis conditioning on rs10982256 (in
DFNB31, associated in WTCCC only) which did not change the pattern of unconditional
results (results not shown).
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