Genome-wide associatio study reveals two new risk ...

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);


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


Observed (-logP)

8

PMooDS=0.0023 !


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


37100

GOLGA4


Observed (-logP)

0.5


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


ZNF506

19600


Observed (-logP)

1!


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


Observed (-logP)

20

0.8

0 CACNA1C

CACNA1C

0 ADCY2C5orf49 FASTKD3 MTRR

7300

7600

2000

Chromosome 5 position (hg18) (kb)

7900


2600

FKBP4


rs4765913 3! P=9.68683e-06


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.


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).


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