1St Latin American Pharmacogenomics and Personalized ... · PDF file12.05.2010 · Instituto Nacional de Medicina Genómica “Genomic diversity of Mexican mestizo and Amerindian groups”

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.


Understanding the Human Genome


*Frazer KA et a. (2009) Nat Rev Genet. 10: 241.

Europeans

Asians

Africans

The Haplotype Structure of the Human Genome

Differs Between Populations


Microarray Technology for Genome-wide Analysis

of Common Variation


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)


Population Structure: Opportunity and Challenge in Genetic Studies in Recently Admixed Populations

Hirschhorn JN and Daly MJ (2005) Nat Rev Genet 6(2):95.


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


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)


Mexican Mestizos Have Amerindian, European and African Ancestral Contributions

*Silva-Zolezzi I et al. PNAS (2009) 106(21):8611-6 .


Mexican Mestizos Have Amerindian, European and African Ancestral Contributions



EUR

EA

AFR

AMI


Regional Differences in Ancestral Contributions Between MexicansAnalysis with 1,814 AIMs


The Effect of Amerindian Ancestral Contribution in the Mexican Mestizo Population Structure


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?



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


2


Using TWO Mexican Groups as Reference

Common Genetic Variation Capture could be Improved if Mexican Genetic Structure is Considered


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


*Hancock DB et a. (2010) Nat Genet. 42 (1): 45-52.

GWAS Meta-analyses of Pulmonary Function and COPD Studies*


Tag SNP Selection in the HHIP Region

Region: 92.71 kb in chr4 from 145,786,623 to 145,879,331


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


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


HHIP Haplotype Diversity

YRI

CEU

CHB+JPT

MEX_LA MEX PDGM

ZAP PDGM


41% 67%

36% 40%

29% 1%

14% 13%

9%

9%

MEX PDGMMEX_LA

1%

2%

CEUZAP PDGM

5%

5%

1%

2%

HHIP Haplotype Diversity


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



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.


CYP2D6 Resequencing in Mexicans

GC= Novel CYP2D6/2D7 gene conversion

Suballeles V to Z are novel

Guerrero (n=48)

Sonora (n=48)

Network analysis


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


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:

Documents

1St Latin American Pharmacogenomics and Personalized ... · PDF file12.05.2010 · Instituto Nacional de Medicina Genómica “Genomic diversity of Mexican mestizo and Amerindian groups”