Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome...
Transcript of Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome...
![Page 1: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/1.jpg)
Wellcome
Trust Case Control Consortium Genome-wide
Association Study of Bipolar Disorder
Nick CraddockDepartment of Psychological Medicine
Cardiff University
![Page 2: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/2.jpg)
![Page 3: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/3.jpg)
![Page 4: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/4.jpg)
![Page 5: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/5.jpg)
WTCCC. Nature 2007; 447: 661-677 & 56 pages of supplementary online material
![Page 6: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/6.jpg)
Bipolar Disorder: Some Terminology
•
Psychosis –
delusions & hallucinations•
Depression –
low mood
•
Mania –
energized mood
Disorder Psychosis Mania Depression
Schizophrenia + +/- +/-
Bipolar disorder +/- + +/-
Unipolar
depression +/- - +
![Page 7: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/7.jpg)
History of WTCCC
UK disease PIs: Common familial diseases
Statisticians: Populationgenetics
African disease PIs: TB &malaria
![Page 8: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/8.jpg)
History of WTCCC
UK disease PIs: Common familial diseases
Statisticians: Populationgenetics
African disease PIs: TB &malaria
Single proposalRing-fenced funds
![Page 9: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/9.jpg)
Bipolar phenotype
•
White UK over age 18 years
•
Interview & case notes
•
RDC–
BPI/ Manic disorder (76%)
–
SABP (15%)–
BPII (9%)
Cardiff (33%)
Birmingham (35%)
Newcastle (9%)
London (15%)
Aberdeen (8%)
![Page 10: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/10.jpg)
WTCCC sample QC procedures
•
Picogreen–
concentration
•
DNA run on gel –
degredation
score
•
Sequenom
panel –
genotyping success
–
Gender check
Select best 2000 samplesfor eachphenotype
![Page 11: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/11.jpg)
WTCCC main Experimentdesign
GeneChip
500k array typed at Affymetrix
South San Francisco Laboratories
![Page 12: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/12.jpg)
Genotype calling
•
Chiamo
algorithm developed by Marchini
& Donnelly for WTCCC
•
Bayesian approach using HapMap knowledge about SNP and calling all
17,000 samples simultaneously
•
Performs better than Affy
algorithms
![Page 13: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/13.jpg)
QC of genotype data•
SNPs–
Poor call rate (<0.95; <0.99)
–
Hardy-Weinberg equilibrium deviation (<6e-7)–
Substantial differences between controls (<6e-7)
469,557SNPs•
Individual samples–
Poor call rates (<0.97)
–
Duplicates/ close relatives–
Substantial non-European ancestry
1868 BD, 2938 controls
![Page 14: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/14.jpg)
Supplementary Figure 5 Multidimensional Scaling (MDS)
![Page 15: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/15.jpg)
Supplementary Table 4: Exclusion summary by collection
![Page 16: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/16.jpg)
![Page 17: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/17.jpg)
![Page 18: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/18.jpg)
Basic statistical tests
•
Armitage
trend test for co-dominant allele effects (1df)
•
General genotype test (2df)
•
Imputation of un-typed SNPs
![Page 19: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/19.jpg)
Robustly known associations are detected
![Page 20: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/20.jpg)
![Page 21: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/21.jpg)
P values
![Page 22: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/22.jpg)
chromosome Region/Postion (Mb) SNP Gene Best p
value
2 115.63-116.11 rs1375144 DPP10 2.43E-06
2 241.23-241.28 rs2953145 RNPEPL1 6.57E-06
2 11.94-12 rs4027132 - 9.69E-06
2 104.41-104.58 rs7570682 - 3.11E-06
3 184.29-184.4 rs683395 LAMP3 2.30E-06
3 32.26-32.33 rs4276227 CMTM8 4.57E-06
6 42.82-42.86 rs6458307 - 4.35E-06
8 34.22-34.61 rs2609653 - 6.86E-06
9 114.31-114.39 rs10982256 DFNB31 8.80E-06
14 103.43-103.62 rs11622475 TDRD9 2.10E-06
14 57.17-57.24 rs10134944 - 3.21E-06
16 23.3-23.62 rs420259 PALB2 6.29E-08
16 51.36-51.5 rs1344484 - 1.65E-06
20 3.7-3.73 rs3761218 CDC25B 6.71E-06
X 110.32 rs975687 CAPN6 2.09E-06
![Page 23: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/23.jpg)
chromosome Region/Postion (Mb) SNP Gene Best p
value
2 115.63-116.11 rs1375144 DPP10 2.43E-06
2 241.23-241.28 rs2953145 RNPEPL1 6.57E-06
2 11.94-12 rs4027132 - 9.69E-06
2 104.41-104.58 rs7570682 - 3.11E-06
3 184.29-184.4 rs683395 LAMP3 2.30E-06
3 32.26-32.33 rs4276227 CMTM8 4.57E-06
6 42.82-42.86 rs6458307 - 4.35E-06
8 34.22-34.61 rs2609653 - 6.86E-06
9 114.31-114.39 rs10982256 DFNB31 8.80E-06
14 103.43-103.62 rs11622475 TDRD9 2.10E-06
14 57.17-57.24 rs10134944 - 3.21E-06
16 23.3-23.62 rs420259 PALB2 6.29E-08
16 51.36-51.5 rs1344484 - 1.65E-06
20 3.7-3.73 rs3761218 CDC25B 6.71E-06
X 110.32 rs975687 CAPN6 2.09E-06
![Page 24: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/24.jpg)
chromosome Region/Postion (Mb) SNP Gene Best p
value
2 115.63-116.11 rs1375144 DPP10 2.43E-06
2 241.23-241.28 rs2953145 RNPEPL1 6.57E-06
2 11.94-12 rs4027132 - 9.69E-06
2 104.41-104.58 rs7570682 - 3.11E-06
3 184.29-184.4 rs683395 LAMP3 2.30E-06
3 32.26-32.33 rs4276227 CMTM8 4.57E-06
6 42.82-42.86 rs6458307 - 4.35E-06
8 34.22-34.61 rs2609653 - 6.86E-06
9 114.31-114.39 rs10982256 DFNB31 8.80E-06
14 103.43-103.62 rs11622475 TDRD9 2.10E-06
14 57.17-57.24 rs10134944 - 3.21E-06
16 23.3-23.62 rs420259 PALB2 6.29E-08
16 51.36-51.5 rs1344484 - 1.65E-06
20 3.7-3.73 rs3761218 CDC25B 6.71E-06
X 110.32 rs975687 CAPN6 2.09E-06
![Page 25: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/25.jpg)
98 regions at p<10-4
![Page 26: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/26.jpg)
Interesting higher ranked hits
•
GABRB1 (GABA A receptor β1)–
rs76803321; p=6.2x10-5
•
GRM7 (glutamate receptor, metabatropic
7)–
rs148517; p=9.7x10-5
•
SYN3 (synapsin
III)–
rs11089599; p=7.2x10-5
![Page 27: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/27.jpg)
The replication challenge
![Page 28: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/28.jpg)
Zeggini
et al. Science 2007 316: 1336-13341.
Type 2 diabetes follow-up
![Page 29: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/29.jpg)
![Page 30: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/30.jpg)
Consistency in top genes?•
No compelling support at DGKH
•
Signals at several genes eg.–
RNPEPL1
•
rs2953174
p=6.42E-06–
DFNB31
•
rs10982256
p=8.80E-06 –
PTPRG
•
rs13074575
p=3.49E-05–
JAM3
•
rs11223704
p=1.49E-04
![Page 31: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/31.jpg)
Is there supportive evidence in WTCCC sample for the set of SNPs?
•
Imputation dataset–
Only SNPs
on platform used by Baum et al
–
Only SNPs
with MAF>0.05–
Only SNPs
with <50% “missing data”
in imputation dataset
Observed p valuesat set of 76 independent SNPs
p values in set of 76 SNPsin random sample 1
p values in set of 76 SNPsin random sample 2
p values in set of 76 SNPsin random sample 1,000,000
cf.
![Page 32: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/32.jpg)
SNPs
significant by pooling in NIMH & Bonn sample
–
5 SNPs
significant in same direction•
JAM3: p=0.00013
•
SLC39A3 p=0.00037•
STAB1 p= 0.016
•
RBMS3 p= 0.029•
BRE p= 0.046
–
These 5 p values•
Significance: p=0.00007 (106
simulations)
![Page 33: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/33.jpg)
Pamela Sklar, Shaun Purcell, Hugh Gurling
and colleagues
•
1461 BPI cases•
2008 controls
![Page 34: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/34.jpg)
![Page 35: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/35.jpg)
![Page 36: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/36.jpg)
AcknowledgementsSklar and Purcell lab membersKimberly ChambertJes FagernessJinbo FanManuel FerreiraBrian GallowayAndrew Kirby Matthew OgdieYan MengDouglas Ruderfer Jennifer StoneKathe Todd-Brown Lauren Weiss
Daly labJulian MallerJosh Korn
Broad Genetic AnalysisPlatformStacey GabrielDavid AltshulerPaul deBakkerBiological Sample Platform
STEP geneticscollaboratorsBernie DevlinSteve FaraoneNan LairdMatt McQueenVishwajit NimgaonkarJordan Smoller
Stanley Foundation of the BroadEd ScolnickLi-Huei TsaiStephen Haggarty
UCLHugh GurlingAndrew McQuillinNick BassJacob LawrenceDavid Curtis
NIMH Genetics InitiativeControl CollectionPablo Gejmanand colleagues
U. EdinburghDouglas BlackwoodWalter MuirKevin McGheeDM MacIntyre
STEP clinical collaboratorsGary SachsRoy PerlisMichael Thase
WTCCCNick CraddockPeter HolmansValenina MoskovinaMick O’DonovanMike Owen
![Page 37: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/37.jpg)
What about the phenotype?
![Page 38: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/38.jpg)
Angst. World Psychiatry 6: 30-21.
![Page 39: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/39.jpg)
Craddock, O’Donovan, Owen. Br J Psychiatry.2007; 190: 200-203
![Page 40: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/40.jpg)
Emil Kraepelin
![Page 41: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/41.jpg)
Reliability
Validity
![Page 42: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/42.jpg)
GenotypePhenotype
Test
Refine phenotype
An iterative approach to the phenotype
Craddock et al.
Mol Psychiatry. 2006; 11:446-58
![Page 43: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/43.jpg)
WTCCC. Nature 2007; 447: 661-677 & 56 pages of supplementary online material
![Page 44: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/44.jpg)
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
Control Bipolar RDC SABP non-SABP
Alle
le fr
eque
ncy
p=6.2 x10-5
N=2938
N=1868
N=279
Phenotyperefinement: index variant in GABRB1
N=1589
![Page 45: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/45.jpg)
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
Control Bipolar RDC SABP non-SABP
Alle
le fr
eque
ncy
p=3.8 x10-6
N=2938
N=1868
N=279
Phenotyperefinement: index variant in GABRB1
N=1589
![Page 46: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/46.jpg)
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
Control Bipolar RDC SABP non-SABP
Alle
le fr
eque
ncy
p=3.8 x10-6 p=0.003
N=2938
N=1868
N=279
Phenotyperefinement: index variant in GABRB1
N=1589
![Page 47: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/47.jpg)
Hypothesis test of specific biological system using refined
phenotype
•
Test variants in GABAA
receptor genes in RDC SABP subset of cases
![Page 48: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/48.jpg)
Mohler. Cell Tissue Res (2006) 326:505–516
![Page 49: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/49.jpg)
Set of SNPs
at GABAA
receptor genes
•
63 SNPs
across the 4p12-13 cluster –
GABRB1, GABRA4, GABRA2, GABRG1•
64 SNPs
across the 5q31-q25 cluster –
GABRB22, GABRA6, GABRA1, GABRG2•
70 SNPs
across the 15q11-q13 cluster –
GABRB3, GABRA5, GABRG3•
22 SNPs
across the Xq28 cluster –
GABRQ, GABR3, GABRE•
21 SNPs
across the pair of genes at 6q15–
GABRR1, GABRR2•
16 SNPs
across the gene at 5q35.1 –
GABRP•
12 SNPs
across the at 3q11.2 –
GABRR3.
![Page 50: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/50.jpg)
Discrepancies v. call rate
0
0.5
1
1.5
2
2.5
3
0.9 0.92 0.94 0.96 0.98 1
Call rate
Cal
l dis
crep
anci
es (%
)
Total error rate (%)
Call rate >99.5%, MAF>0.05: genotyping agreement 99.95%
![Page 51: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/51.jpg)
LD S
truct
ure
-Log
(p-v
alue
)
0
12
3
45
6
4
rs7680321p=3.6x10-6
rs6414684p=1.1x10-6
4p12-13 cluster
10-6
10-4
10-2
GABRB1GABRA4GABRA2GABRG1
![Page 52: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/52.jpg)
LD S
truct
ure
-Log
(p-v
alue
) 1
3
5
10-4
10-2
rs17561681p=2.0x10-4
rs890319p=5.0x10-4
GABRG3GABRA5GABRB3
15q11-q13 cluster
![Page 53: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/53.jpg)
-Lg(
p-va
lue)
1
3
GABRR3
-Log
(p-v
alue
)
10-2
GABRR3
rs854579p=4.4x10-3
![Page 54: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/54.jpg)
Gene Most significant SNP
Controls frequency of risk allele
SABP v. controls OR (95% CI)
SABP v. controls allelic p value
SABP v. Non-SABP BD allelic p value
Additional evidence over and above index SNP(p value)
GABRB1 rs6414684 0.4910 1.56 (1.27-1.91)
1.1 x10-6 0.001 0.0041
GABRB2 - - - NS NS NS
GABRB3 rs890319 0.3231 1.38(1.11-1.71)
5.0 x10-4 0.0059 0.012
Association at GABAA
β
receptor genes in SABP cases compared with controls and with non-SABP bipolar cases
Independent evidence at β
receptor genes : p=0.00024
![Page 55: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/55.jpg)
Hypothesis test of specific biological system using refined
phenotype
•
Independent of index signal there is strong support for system involvement–
p=4.8x10-5
•
Several genes implicated–
GABRB1, GABRB3, GABRA4, GABRA5 GABRR1
![Page 56: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/56.jpg)
What are implications?
•
More biologically homogeneous sub-set of bipolar cases
•
Can provide a theoretical base to guide treatment choice
•
Can help to explain commonly observed “co-morbidities”
with bipolar disorder
–
Anxiety/ panic–
Alcohol abuse
![Page 57: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/57.jpg)
What does this mean for diagnosis?
![Page 58: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/58.jpg)
Prototypical Prominent psychotic Prototypical Schizophrenia and affective features Mood Disorder
Most patients seen in clinical practice
Schizophrenia Mood disorderRDC Schizoaffective
Disorder, bipolar
X A C B Y
Phenotypic Specificity of genetic risk
![Page 59: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/59.jpg)
Prototypical Prominent psychotic Prototypical Schizophrenia and affective features Mood Disorder
Most patients seen in clinical practice
Schizophrenia Mood disorderDSMSA
X A C B Y
Phenotypic Specificity of genetic risk
![Page 60: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/60.jpg)
Marneros
et al.European Psychiatry 2005; 20: 315–320
Acute and transient psychotic disorders (ICD10)
•Cycloid psychoses (Germany)•Psychogenic psychoses (Scandinavia)•Bouffée délirante
(France)
•Good prognosis schizophrenia (USA)
![Page 61: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/61.jpg)
Br J Psychiatry 2005; 186: 364-366
19th
Century 21st
Century
![Page 62: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/62.jpg)
World Psychiatry June 2007
![Page 63: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/63.jpg)
Take Home Messages•
The beginning …
–
Some of genes/ systems being implicated relate to known hypotheses
–
Close attention to QC essential
–
Multiple large samples needed –
collaboration
–
Think beyond traditional diagnostic categories
. . .
![Page 64: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/64.jpg)
Acknowledgements
![Page 65: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/65.jpg)
Statistical analyses of main WTCCC dataset
Management committee
Manuscript
![Page 66: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/66.jpg)
Bipolar disorder group
![Page 67: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/67.jpg)
Some comments about controls
•
Non-screened controls
•
Common controls within an experiment
•
Common controls across experiments
![Page 68: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/68.jpg)
Green et al, Arch Gen Psychiatry. 2005;62:1081-1088
![Page 69: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/69.jpg)
Green et al, Arch Gen Psychiatry. 2005;62:1081-1088
![Page 70: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/70.jpg)
Green et al, Arch Gen Psychiatry. 2005;62:1081-1088
DISC1
![Page 71: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/71.jpg)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
1 2 3 4 5 6 7 8 9 10 11 12
1 2 3 4 5 6
1 2I
II
II
VI
V
ASSOCIATION OF A BALANCED AUTOSOMAL TRANSLOCATION t(1;11)WITH MAJOR MENTAL ILLNESS
Schizophrenia Bipolar Disorder
RecurrentMajor
Depression
AdolescentConduct Disorder
Anxiety, Alcoholism,Minor Depression
Translationt(1;11) Carrier
St Clair et al. Lancet 1990; 336:13-6; Blackwood et al. Am J Hum Genet. 2001; 69:428-33
![Page 72: Wellcome Trust Case Control Consortium Genome-wide Association Study … · 2009-06-11 · Wellcome Trust Case Control Consortium Genome-wide Association Study of Bipolar Disorder](https://reader033.fdocuments.us/reader033/viewer/2022041911/5e6768cd1903b176d92b080b/html5/thumbnails/72.jpg)