Analysis of Complex Genetic Diseases

David Duffy

QIMR logo QIMR Berghofer Medical Research Institute

What is a Complex Genetic Disease

What kind of groups do we study

Phenometric Studies

Relatedness of disease cases

Ancestral kinship and cancer on Lastovo Island, Croatia [Rudan 2001]:

Kinship of female cancer cases

Path analysis

Tambs et al [1992] collected blood pressure measurements and familial relationships for 74994 Norwegians:

Stealth path model

They concluded 47% of the variation in systolic BP was genetic, only 2% is due to shared family environment and 51% is due to unshared environment.

Genometric Studies

Reasons to be cheerful

Causes of difficulty

Allelic Heterogeneity

The Human Genome Mutation Database lists 347 known mutations in BRCA1:

BRCA1 mutation map

Locus Heterogeneity

In humans, asthma has been reported associated with variants in:

ADA ADAM33 ADRB2 ALOX5 BCL6 C3 CFTR CYSLTR2
DCP1 ELF5 FCER1B FCER2 Gm HLA Hp
IFNG IL4 IL4R IL9 IL10 IL12B IL13 LTC4S PAFAH
SCYA5 SPINK5 TCRAD TGFB TLR4 TNFA UGB UGRP1

Low Trait Locus Penetrances

Initial estimates of the association between the IL4R*Q576R SNP and atopy were high.

Pooled estimates from multiple studies are:

Odds Ratio QR 1.02
Odds Ratio QQ 1.30

IL4R*Q576R genotypes and atopy
Study Trait QQRQRRR
Hershey Control 25 4 10.10
Atopy 712 10.35
Howard Control 7336 50.20
Asthma 10739 70.17
Kauppi Control 8237110.23
Asthma 12141 50.15
SandfordControl 9543 50.19
Asthma 14569 70.19
Ziani Control 5138 30.24
Atopy 4430190.37
Dupre Control1500.16
Atopy 750.18
Tanaka Control10021 10.09
Atopy 22747 30.10

Gene by Environment Interaction

ERCC2 genotype, cigarette smoking and lung cancer risk in 2575 cases and controls [Zhou et al 2002]:

G x E interaction

Between-study linkage heterogeneity 1

C6 IgE lods

Between-study heterogeneity 2

C11 IgE lods

Between-population trait locus heterogeneity

Between-population marker locus heterogeneity

Conclusions