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Instituto Nacional de Medicina Genómica
“Genomic diversity of Mexican mestizo
and Amerindian groups”
Irma Silva Zolezzi, PhD.
1St Latin American Pharmacogenomics and Personalized Medicine Congress
May 12th, 2010. San Juan , Puerto Rico.
Instituto Nacional de Medicina Genómica
Understanding the Human Genome
Instituto Nacional de Medicina Genómica
*Frazer KA et a. (2009) Nat Rev Genet. 10: 241.
Europeans
Asians
Africans
The Haplotype Structure of the Human Genome
Differs Between Populations
Instituto Nacional de Medicina Genómica
Microarray Technology for Genome-wide Analysis
of Common Variation
Instituto Nacional de Medicina Genómica
Cholesterol
Obesity
Myocardial Infarction
Long-QT syndrome
Atrial Fibrilation
Type 2 Diabetes
Prostate cancer
Breast cancer
Colon cancer
Coronary Heart Disease
Age-related Macular Degeneration
Crohn’s Disease
Type 1 Diabetes
SLE
Asthma
Restless leg syndrome
Gallbladder Disease
Multiple Sclerosis
Rheumatoid Artritis
Glaucoma
KCNJ11
20032000
PPARG
2001
IBD5
NOD2
2005 20062002
CTLA4
2004
PTPN22
CD25
IRF5
PCSK9
CFH
2007
FGFR2
TNRC9
MAP3K1
LSP1
8q24
CDKN2B/A
8q24 (n=6)
ATG16L1
5p13
10q21
IRGM
NKX2-3
IL12B
3p21
1q24
PTPN2
TCF2
CDKN2B/A
IGF2BP2
CDKAL1
HHEX
SLC30A8
TBL2
TRIB1
KCTD10
ANGLPT3
GRIN3A
MEIS1
LBXCOR1
BTBD9
C3
8q24
ORMDL3
4q25
TCF2
GCKR
FTO
C12orf30
ERBB3
KIAA0350
CD226
16p13
PTPN2
SH2B3
ITGAM
BLK
HMGA2
GDF5-UQCC
HMPG
CRAC1
JAZF1
CDC123
ADAMTS9
THADA
WSF1
LOXL1
GLUT9
L7R
TRAF1/C5
STAT4
4q27
ABCG8
MLXIPL
GALNT2
PSRC1
NCAN
NOS1AP
IFIH1
PCSK9
CFB/C2
LOC387715
8q24
IL23R
TCF7L2
To date: > 900 loci have been associated
Genes Associated to Complex
Traits and Diseases (December 2007)
Instituto Nacional de Medicina Genómica
Population Structure: Opportunity and Challenge in Genetic Studies in Recently Admixed Populations
Hirschhorn JN and Daly MJ (2005) Nat Rev Genet 6(2):95.
Instituto Nacional de Medicina Genómica
The Mexican Genome Diversity Project
The aim of the project is characterize the genetic structure of
Mexicans to improve the design and analysis of GW and targeted
genetic association studies
The final goal is to build and annotate a HapMap-like database
with ~1.3 million SNP genotypes of 300 Mexican Mestizos and
120 Amerindians from 3 different ethnic groups
It started in 2005 funded by the Mexican Federal Government
We have completed all genotyping and the first set of analyzed
data (~100,000 genotypes) is publicly available
Instituto Nacional de Medicina Genómica
The Mexican Genome Diversity Project
SONORA DURANGO
ZACATECAS
TAMAULIPAS
CAMPECHE
VERACRUZGUERRERO OAXACA
YUCATÁN
DURANGO
CAMPECHE
OAXACA
GUANAJUATO
MESTIZO
GROUPS (100K
/ 1.3M)
AMERINDIAN
GROUP
ZAPOTECOS
(100K/ 1.3 M)
MESTIZO
GROUP (≈1M)
AMERINDIAN
GROUPS
TEPEHUANES
MAYAS
(≈1M)
Instituto Nacional de Medicina Genómica
Mexican Mestizos Have Amerindian, European and African Ancestral Contributions
*Silva-Zolezzi I et al. PNAS (2009) 106(21):8611-6 .
Instituto Nacional de Medicina Genómica
Mexican Mestizos Have Amerindian, European and African Ancestral Contributions
*Silva-Zolezzi I et al. PNAS (2009) 106(21):8611-6 .
Instituto Nacional de Medicina Genómica
EUR
EA
AFR
AMI
*Silva-Zolezzi I et al. PNAS (2009) 106(21):8611-6 .
Regional Differences in Ancestral Contributions Between MexicansAnalysis with 1,814 AIMs
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The Effect of Amerindian Ancestral Contribution in the Mexican Mestizo Population Structure
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Sharing of Common Haplotypes between Mexican Mestizo and HapMap Groups (%)
CEU JPT+CHB YRI CEU+JPT+CHB CEU+JPT+CHB+YRI
GUA 81 75 64 93 96
GUE 79 76 65 93 96
SON 82 71 63 94 97
VER 80 75 64 93 96
YUC 81 74 64 93 96
ZAC 81 73 64 93 97
Average 81 74 64 93 96
How Much Common Genetic Variation is Captured if only HapMap Info is Used?
*Silva-Zolezzi I et al. PNAS (2009) 106(21):8611-6 .
Instituto Nacional de Medicina Genómica
Common Genetic Variation Capture could be Improved if Mexican Genetic Structure is Considered
Sharing of Common Haplotypes between Mexican Mestizos (%)
GUA GUE SON VER YUC ZAC
GUA 86 87 87 87 88
GUE 88 87 88 87 88
SON 83 8 82 83 84
VER 87 86 87 87 88
YUC 87 85 87 86 87
ZAC 85 83 87 85 85
Average 86 84 87 86 86 87
Using ONLY ONE Mexican Group as Reference
*Silva-Zolezzi I et al. PNAS (2009) 106(21):8611-6 .
2
Instituto Nacional de Medicina Genómica
Using TWO Mexican Groups as Reference
Common Genetic Variation Capture could be Improved if Mexican Genetic Structure is Considered
*Silva-Zolezzi I et al. PNAS (2009) 106(21):8611-6 .
Sharing of Common Haplotypes between Mexican Mestizos (%)
GUA
GUE
GUA
SON
GUA
VER
GUA
YUC
GUA
ZAC
GUE
SON
GUE
VER
GUE
YUC
GUE
ZAC
SON
VER
SON
YUC
SON
ZAC
VER
YUC
VER
ZAC
YUC
ZAC
GUA 97 96 96 96 96 97 97 96 96 96
GUE 96 96 96 96 96 96 96 96 96 96
SON 93 93 94 94 92 93 93 93 94 94
VER 96 97 96 97 97 96 96 96 97 97
YUC 95 96 96 96 96 95 96 96 96 96
ZAC 95 96 95 95 96 95 95 96 96 95
Avg 95 96 95 95 96 97 95 95 95 96 96 97 95 96 96
Instituto Nacional de Medicina Genómica
*Hancock DB et a. (2010) Nat Genet. 42 (1): 45-52.
GWAS Meta-analyses of Pulmonary Function and COPD Studies*
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Tag SNP Selection in the HHIP Region
Region: 92.71 kb in chr4 from 145,786,623 to 145,879,331
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Criteria for Tag SNPs Selection
Tagger program implemented in Haploview v4.2
HapMap v3 R2 genotypes for al HapMap populations
SNPs with MAF>0.05
Maximum tagging distance 500Kb, r2>0.8
Tagging method using 2-marker haplotypes
We used 4 HapMap populations and 2 from the MGDP:
CEU+TSI, 200 individuals of European ancestry
CHB + JPT, 90 individuals of East Asian ancestry
YRI, 60 individuals of African ancestry
MEX_LA, 52 individuals of Mexican ancestry from LA, CA, USA
MEX_PDGM, 300 Mexican mestizos
ZAP_PDGM, 44 Zapotecas from Oaxaca , México
Instituto Nacional de Medicina Genómica
LD Structure in the HHIP region
YRI42/59
informative SNPs
12 ND
2 Monomorphic
3 MAF<0.05
CEU41/59
informative SNPs
12 NI
5 Monomorphic
1 MAF<0.05
CHB+JPT41/59
informative SNPs
12 ND
4 Monomorphic
2 MAF<0.05
MEX_LA41/59
informative SNPs
12 ND
4 Monomorphic
2 MAF<0.05
MEX MGDP46/59
Informative SNPs
1 ND
5 Monomorphic
7 MAF<0.05
ZAP MGDP32/59
Informative SNPs
1 ND
13 Monomorphic
11 MAF<0.05
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HHIP Haplotype Diversity
YRI
CEU
CHB+JPT
MEX_LA MEX PDGM
ZAP PDGM
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41% 67%
36% 40%
29% 1%
14% 13%
9%
9%
MEX PDGMMEX_LA
1%
2%
CEUZAP PDGM
5%
5%
1%
2%
HHIP Haplotype Diversity
Instituto Nacional de Medicina Genómica
Tagging of HHIP in different populations
Population Tag SNPs Untagged
SNPs
Total SNPs
YRI 8 8 16 (47)
CEU 7 3 10 (46)
CHB+JPT 5 4 8 (45)
MEX_LA 8 3 11 (43)
MEX_PDGM 6 1 7 (46)
ZAP_PDGM 3 1 4 (33)
Coverage of common diversity (>5%)
in Mexicans*
Reference population(s) # Tag SNPs
81% CEU 10
93% CEU+CHB+JPT 15
96% CEU+CHB+JPT+YRI 24
>98% CEU+CHB+JPT+YRI+MEX_LA 30
>98% MEX_PDGM 7
*Silva-Zolezzi I et al. PNAS (2009) 106(21):8611-6 .
Instituto Nacional de Medicina Genómica
CYP2D6 Resequencing in Mexicans
• The Cytochrome P-450 is a superfamily of phase I drug-metabolizing
enzymes.
• CYP2D6 is of central importance in the metabolism of a large number of
commonly prescribed drugs (antidepressants, antipsychotics,
antihypertensives, b-adrenergic blocking agents and antiarrhythmics).
• It shows a high degree of interindividual and interethnic variability, primarily
due to genetic polymorphisms,
• This variability leads to distinct functional phenotypes termed ultrarapid
(UM), extensive (EM), intermediate (IM) and poor metabolizer (PM).
• To characterize the allele distribution in Mexicans and to optimize the
identification of new variants we resequenced CYP2D6 in the MGDP
subpopulations with the highest Amerindian (GUE) and European (SON)
ancestral contributions.
Instituto Nacional de Medicina Genómica
CYP2D6 Resequencing in Mexicans
GC= Novel CYP2D6/2D7 gene conversion
Suballeles V to Z are novel
Guerrero (n=48)
Sonora (n=48)
Network analysis
Instituto Nacional de Medicina Genómica
Which are the Main Goals of the MGDP?
Improve the design of GW and targeted association studies in
Mexicans and related populations:
a) Better selection of Tag SNPs (eg.COPD)
b) Correction of population stratification
c) Adequate definition of regions for fine mapping and
re-sequencing strategies (eg. CYP2D6)
Develop an adequate infrastructure and human resources to
work with massive genotype data
Promote equal access to genetic information of Amerindian
and Mexican Mestizos for Mexico and other Latin American
countries to optimize genomic research
Instituto Nacional de Medicina Genómica
Dr. Gerardo Jiménez-Sánchez
Research Group
Eros Balam
Alejandra Contreras
Laura deL Bosque
Alfredo Hidalgo
Gabriela Mercado
Irma Silva Zolezzi
David Velázquez
Luis A Alfaro
Tulia Monge
INMEGEN ParticipantsCore Facilities:
High-throughput
genotyping
Fabiola Morales
Leticia Sebastián
Laura Uribe
Gisella Ortiz
José Luis Cruz
Sequencing
Karol Carrillo
Salvador Hernández
Haydee Miranda
Computational Genomics
Research Group
Jesús K. Estrada
Juan Carlos Fernández
Claudia Rangel
Enrique Hernández
Divisions:
Research and
Education
Santiago March
Alejandro López
José Bedolla
Vinculation
Eduardo Barrientos
César Lara
Eunice Rendón
Alberto Arellano
Technological
Development
Carlos Dávila
Rodrigo Goya
Isaac Vera
Special thanks to: