1: rs10994336-T: PMeta=2.34E-08 (OR=1.27); PPGC=4.01E-09 (OR=1.35); PMooDS=0.171 (OR=1.11); Ferreira et al. (2008)1! 2: rs4948418-T: ...
Mühleisen, Leber, Schulze et al., Genome-wide association study reveals two new risk loci for bipolar disorder
Supplementary Figures a 1: rs10994336-T: PMeta=2.34E-08 2: rs4948418-T: PMeta=5.60E-07 3: rs10994397-T: PMeta=2.86E-10 4: rs1938526-G: PMeta=8.55E-10
(OR=1.27); (OR=1.23); (OR=1.29); (OR=1.27);
PPGC=4.01E-09 (OR=1.35); PMooDS=0.171 PPGC=7.02E-08 (OR=1.32); PMooDS=0.281 PPGC=5.54E-10 (OR=1.35); PMooDS=0.032 PPGC=1.85E-09 (OR=1.32); rs10994415 ( CEU ) PMooDS=0.034
12
Ferreira et al. (2008)1! Chen et al. (2011)2! PGC-BD (2011)3! Ferreira et al. (2008)1!
80
rs10994415-C! Pmeta =6.88E-11 (OR=1.27)! PPGC =6.97E-10 (OR=1.31)! rs10994415 PP=6.87608e-11 (OR=1.15)! MooDS =0.0096 3! ! 4!
9
0.8 0.5
60
1!
r2
2!
6
40
3
20
0
0 ANK3
CDC2 CDK1
ANK3
61700
62000
RHOBTB1
62300
Chromosome 10 position (hg18) (kb)
3
Recombination rate (cM/Mb)
Observed (-logP)
(OR=1.11); (OR=1.08); (OR=1.17); (OR=1.16);
Mühleisen, Leber, Schulze et al., Genome-wide association study reveals two new risk loci for bipolar disorder
b 1: rs12576775-G: Pmeta=4.46E-09 (OR=1.17); PPGC=2.66E-08 (OR=1.18); PMooDS=0.0294 (OR=1.13); PGC-BD (2011)3; PGC-CD (2013)4! 2: rs12290811-A: Pmeta=1.09E-09 (OR=1.19); PPGC=9.25E-08 (OR=1.19); PMooDS=0.0023 (OR=1.19); Ferreira et al. (2008)1! 3: rs2175420-T: Pmeta=6.77E-06 (OR=1.13); PPGC=7.45E-06 (OR=1.15); PMooDS=0.175 (OR=1.07); PGC-BD (2011)3! ! rs12290811 ( CEU )
10
80
rs12290811-A!
rs12290811 2! Pmeta =1.09E-09 (OR=1.19)! P=1.09187e-09 PPGC =9.25E-08 (OR=1.19)! 1!
0.8
(OR=1.19)!
0.5
6
60
r2
3!
40 4
20 2
0
0 ODZ4
ODZ4
78500
78800 Chromosome 11 position (hg18) (kb)
79100
Recombination rate (cM/Mb)
Observed (-logP)
8
PMooDS=0.0023 !
Mühleisen, Leber, Schulze et al., Genome-wide association study reveals two new risk loci for bipolar disorder
c 1: rs9834970-C: PMeta=4.81E-08 (OR=1.12); PPGC=6.19E-06 (OR=1.11); PMooDS=0.0014 (OR=1.15); Chen et al. (2011)2; Goes et al. (2012)5! 2: rs6550435-G: PMeta=2.05E-08 (OR=1.13); PPGC=4.80E-06 (OR=1.12); PMooDS=7.16E-04 (OR=1.15); PGC-BD (2011)3; Green et al. (2012)6!
rs6550435 ( CEU ) rs6550435-G! Pmeta =2.05E-08 (OR=1.13)! PPGC =4.80E-06 (OR=1.12)! rs6550435 2! PMooDS=7.16E-04 (OR=1.15)! P=2.04749e-08 ! 1!
8
80 0.8
60
6 r2 40 4
20
2
0
0 STAC
LBA1 TRANK1
DCLK3
EPM2AIP1 LRRFIP2 MLH1
36500
36800 Chromosome 3 position (hg18) (kb)
37100
GOLGA4
Recombination rate (cM/Mb)
Observed (-logP)
0.5
Mühleisen, Leber, Schulze et al., Genome-wide association study reveals two new risk loci for bipolar disorder
d 1: rs1064395-A: PMeta=2.25E-06 (OR=1.14); PPGC=0.00216 (OR=1.10); PMooDS=2.76E-05 (OR=1.25); Cichon et al. (2011)7!
rs2011503 ( CEU ) rs2011503-C! rs2011503 Pmeta =8.79E-08 (OR=0.87)! PPGC =4.77E-04 (OR=0.90)! P=8.79265e-08 PMooDS=2.20E-06 (OR=0.78)! !
8
80 0.8 0.5
6
60
r2 4
40
2
20
0
0 UPF1
SFRS14 LASS1
TMEM161A
ARMC6
GDF1
SLC25A42
COPE
TM6SF2
SUGP1 SF4
MEF2B
KIAA0892 MAU2
RFXANK
GATAD2A TSSK6
LPAR2
NDUFA13
GMIP
FLJ44968
NR2C2AP
HOMER3
ATP13A1 ZNF101
CILP2
NCAN NCAN
DDX49
PBX4
ZNF14
HAPLN4
19000
19300 Chromosome 19 position (hg18) (kb)
ZNF506
19600
Recombination rate (cM/Mb)
Observed (-logP)
1!
Mühleisen, Leber, Schulze et al., Genome-wide association study reveals two new risk loci for bipolar disorder
e 1: rs1006737-A: PMeta=9.80E-05 (OR=1.09); PPGC=1.73E-05 (OR=1.11); PMooDS=0.643 (OR=1.02); Ferreira et al. (2008)1! 2: rs1024582-A: PMeta=1.76E-04 (OR=1.08); PPGC=4.41E-05 (OR=1.11); PMooDS=0.614 (OR=1.02); Ferreira et al. (2008)1! 3: rs4765913-A: PMeta=9.69E-06 (OR=1.12); PPGC=1.35E-06 (OR=1.15); PMooDS=0.568 (OR=1.03); PGC-BD (2011)3!
rs4765913 ( CEU )
8
80 rs4765913-A! Pmeta =9.69E-06 (OR=1.12)! PPGC =1.35E-06 (OR=1.15)! PMooDS=0.568 (OR=1.03)! !
6
0.8 0.5
60
Observed (-logP)
r2
1!
4
40
2! rs17826816 ( CEU ) 80
8
rs17826816 P=9.89449e-09
2
0.5
60
6 r2 40 4
2
0 CACNA2D4
DCP1B
20
LRTM2 0
Recombination rate (cM/Mb)
Observed (-logP)
20
0.8
0 CACNA1C
CACNA1C
0 ADCY2C5orf49 FASTKD3 MTRR
7300
7600
2000
Chromosome 5 position (hg18) (kb)
7900
2300 Chromosome 12 position (hg18) (kb)
2600
FKBP4
Recombination rate (cM/Mb)
rs4765913 3! P=9.68683e-06
Mühleisen, Leber, Schulze et al., Genome-wide association study reveals two new risk loci for bipolar disorder
Supplementary Figure 1 | Association results for previously reported risk loci for BD displayed in the order of their significance level in the present study. (a) ANK3 (10q21.2), (b) ODZ4 (11q14.1), (c) TRANK1 (3p22.2). (d) NCAN (19p13.11), and (e) CACNA1C (12p13.33). Regional association plots for SNPs were generated using SNAP8 and data for LD (red) and recombination frequency (blue line) from the 1000 Genomes Project. SNP identifiers and original references of the known risk variants as well as their association results in the present study are shown on top of the plot. The chromosomal positions of the known variants are marked by numbers that refer to the numbers on top of the plot. The indicated alleles are the effect alleles (A1) from the present study. For SNPs in ANK3, ODZ4, and TRANK1, further details are provided by Supplementary Tables 1, 2, and 5. The following abbreviations are used: Pmeta, genomic control P-value (PGC) of the fixed-effects meta-analysis using the MooDS-PGC samples (Methods); PPGC: P-value of the fixed-effects meta-analysis using the published PGC-BD data7 only; PMooDS: P-value of the fixed-effects metaanalysis using the MooDS data only.
Mühleisen, Leber, Schulze et al., Genome-wide association study reveals two new risk loci for bipolar disorder
Supplementary Figure 2 | Multi-dimensional scaling analysis (MDS) during the second QC. To identify potential population stratification, we used the first two MDS dimensions. Population outliers were visually determined and excluded before the third QC (Methods and Supplementary Table 9). The plot shows the population structures when all seven MooDS samples are analyzed in parallel. In addition, we performed a MDS analysis between patients and controls within each MooDS sample. The significant MDS dimensions were used as covariates in the sample-specific association analyses (Methods).
Mühleisen, Leber, Schulze et al., Genome-wide association study reveals two new risk loci for bipolar disorder
Supplementary Tables Supplementary Table 1 | 35 SNPs (PGC1. SNPs are sorted according to their genomic control P-values (PGC) from the fixed-effects metaanalysis using the MooDS-PGC samples (Methods). Genome-wide significance is defined by the -8 formal threshold of PGC