Analysis of Complex Genetic Diseases

David Duffy

QIMR Berghofer Medical Research Institute

What is a Complex Genetic Disease

• Does not exhibit a simple Mendelian pattern of inheritance
• Likely to be oligogenic or polygenic
• Penetrance of any single gene not high
• Involves multifactorial causation (genes, environment)

What kind of groups do we study

• Population isolates eg Amish, Tristan Da Cunha, Iceland, Sardinia
• Admixed populations ie Caucasian/Japanese intermarriage in Hawaii.
• Migration of populations into different environments eg Tokelauan islanders and asthma; American blacks and sickle cell anaemia.
• Families (nuclear or multigenerational)
• Pairs of relatives

Phenometric Studies

• "General" population samples eg degree of relatedness of pairs of cancer cases compared to that of pairs of controls eg prostate cancer in Utah (expressed as mean coefficient of relationship so clustering in terms of genetic distance); all cancers and sharing surnames in UK.
• Weinberg proband-control studies eg CASH study of breast cancer, Cooke's studies of asthma.
• Path analysis of family material eg Tambs on hypertension
• Twin studies
• Segregation analysis of family material eg Morton on total sIgE

Relatedness of disease cases

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

Path analysis

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

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

• Genetic linkage analysis
  • Parametric ("lod" score) linkage analysis
  • Combined segregation-linkage analysis
  • MOD and WROD score linkage analysis
  • Nonparametric (trait locus model free) linkage analysis
  • Variance components linkage analysis
• Genetic association analysis of unrelated individuals
  • Conventional case-control or cohort analyses
  • Genome control
  • Haplotype inference
• Genetic association analysis of families
  • Mixed-effects association analysis
  • Transmission-based tests
  • "ABAW" based approaches

Reasons to be cheerful

• The common disease-common gene hypothesis
• The density of SNPs now available
• The power of association analysis cf linkage analysis
• Haplotype blocks (fine recombination structure)
• Larger studies and metaanalyses
• Subsetting of disease eg familial breast cancer
• A few recent successes

Causes of difficulty

• Trait locus allelic heterogeneity
• Low trait locus penetrances
• High trait allele frequency: Gene x Gene interaction
• Low trait allele frequency: Between-family heterogeneity
• Between-population trait locus heterogeneity
• Between-population marker locus heterogeneity
• Gene x Environment interaction
• Gene-Environment correlation

Allelic Heterogeneity

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

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	QQ	RQ	RR	R
Hershey	Control	25	4	1	0.10
	Atopy	7	12	1	0.35
Howard	Control	73	36	5	0.20
	Asthma	107	39	7	0.17
Kauppi	Control	82	37	11	0.23
	Asthma	121	41	5	0.15
Sandford	Control	95	43	5	0.19
	Asthma	145	69	7	0.19
Ziani	Control	51	38	3	0.24
	Atopy	44	30	19	0.37
Dupre	Control	150			0.16
	Atopy	75			0.18
Tanaka	Control	100	21	1	0.09
	Atopy	227	47	3	0.10

Gene by Environment Interaction

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

• ERCC2 (19q13.2) codes for a DNA repair protein (Type D xeroderma pigmentosum).
• ERCC2*312Asp previously reported to increase risk in light but not heavy smokers.

Between-study linkage heterogeneity 1

Between-study heterogeneity 2

Between-population trait locus heterogeneity

• APOE*E4 is the ancestral APOE allele: common in Africans
• APOE*E4 is associated with increased risk of late-onset Alzheimer's Disease
  • In Europeans
  • In Asians
  • Not in Africans
  • Not in African-Americans

Between-population marker locus heterogeneity

• Especially of interest for linkage disequilibrium mapping
• May or may not be a problem
• Several methods for dealing with it

Conclusions