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Contents

Contributors

Foreword

SECTION 1 Introductory principles

1 Genes and their expression

What is a gene?

The transcriptome and the proteome

Gene expression

Transcriptional regulation

Promoters and the general transcription machinery

RNA polymerases

Cis-regulatory elements

Enhancers and repressors

Locus control regions

Boundary elements/insulators

Matrix attachment sites

A current view of enhancer action

Transcriptional regulation and chromatin remodeling

Chromatin structure

Chromatin modification and transcription

Histone acetyl transferase activity

ATP-dependent chromatin remodeling activity

Epigenetic regulation through DNA modification

Nuclear compartmentalization and dynamics

Transcriptional regulation and disease

Concluding remarks

REFERENCES

2 Epigenetic modification of chromatin

Location, location, location!

Chromatin

Histone modification

Chromatin remodeling

DNA modification

Transcriptional repression by DNA methylation

Alpha-thalassemia/mental retardation syndrome; ATR-X

Rett syndrome – RTT

DNA methylation and cancer

Myeloid/lymphoid or mixed lineage leukemia

Diseases of genomic imprinting

Conclusions

Glossary

Acknowledgments

REFERENCES

3 Population genetics and disease

Introduction

Genetic variation and genetic disease

Hardy–Weinberg and genetic drift

The coalescent

Selection

Multi-locus models and linkage disequilibrium

Measures of LD

Models of complex disease

Common disease-common variant . . . or not?

Allelic heterogeneity at Mendelian loci

Experimental results

Sex Effects

Gene (x) environment interaction (GEI)

Epistasis

Summary

REFERENCES

4 Mapping common disease genes

Introduction

What is "gene mapping" and why is it useful?

Variation and disease

Principles of gene mapping

Linkage mapping in families

Experimental designs

Association studies

Measures of linkage disequilibrium

Power or sample size in association studies

Sample collection and population stratification

SNP selection

Analysis of association studies

Multiple testing

Linkage meets association

Quantitative traits

Some success stories

Future considerations and prospects

Is there a future for linkage analysis?

Impact on health

REFERENCES

5 Population diversity, genomes and disease

Introduction

Genome-wide LD (linkage disequilibrium) patterning

Bottlenecks

Admixture

Admixture mapping

Localized LD patterning

Recombination and the shaping of localized LD

Selection and the shaping of localized LD

HapMap and tagging SNPs

Tagging with HapMap data

Example of tSNP design using SCN8a

Fine localization following initial association

The use of HapMap data to identify evidence for selection

Conclusions

REFERENCES

6 Study design in mapping complex disease traits

Introduction

Goals of complex disease trait mapping

Important preliminary steps

Review of evidence for a genetic effect

Realistic estimation of study power

Genetic architecture of common complex disease: implications for study design

Genetic effect sizes in complex disease: implications for study strategy

Identifying moderate to large genetic effects

Allele frequency of disease susceptibility variants: implications for study strategy

What approaches are possible to detect rare variants?

Number of genetic variants contributing to genetic etiology: implications for study strategy

Genetic heterogeneity: implications for study strategy

Characteristics of populations in determining suitability for genetic studies

Special populations

Inbred founder populations

Admixed populations

Population biobanks

Family-based and population-based strategies

Family-based approaches

Population-based approaches

Direct association

Indirect association

Expression quantitative trait loci (QTL)

Interaction effects

Gene–gene interactions (epistasis)

Gene–environment interactions

Mendelian randomization

Interpretation of results: causal inference

Experimental evidence

Consistency of association

Biological plausibility

Possible interpretation of different types of variant

Strength of association

Interpretation of results: reporting and characterizing genetic effects

International collaboration

Conclusions

REFERENCES

7 Diseases of protein misfolding

Introduction

The nature of protein misfolding

Protein misfolding and its consequences for disease

The structure and mechanism of amyloid formation

A generic description of amyloid formation

The fundamental origins of amyloid disease

Approaches to therapeutic intervention in amyloid disease

Concluding remarks

REFERENCES

8 Aging and disease

Is achieving extreme old age worthwhile? the centenarian phenotype

The relative contributions of genes, environment and luck to how we age

The familiality of exceptional longevity

A proposed multifactorial model for exceptional longevity and exceptional survival phenotypes

Genes predisposing to exceptional longevity

Conclusion

REFERENCES

9 The MHC paradigm: genetic variation and complex disease

Features of the MHC

The MHC and disease: general considerations

Autoimmune diseases

Immunopathology

Environmental effects

Non-MHC genes are also involved

Mechanisms for MHC associations

Infectious diseases

Other MHC-associated diseases

The price of disease resistance

REFERENCES

10 Lessons from single gene disorders

Introduction

Locus and allelic heterogeneity: the good and the bad

Penetrance, expressivity and genetic modifiers

The difficult hunt for modifier loci

Mutational spectra: how many types of functional variant?

Long distance regulators

The remarkable case of preaxial polydactyly: gain of function mutations operating on the sonic hedgehog gene from a vast distance

Another new mutation target: exonic splicing enhancers

The genome sequence pinpoints novel potential regulatory variants

A plethora of functional mutations

The study of monogenic subsets give mechanistic insights into common disease, leading to novel therapeutic approaches

Familial hypercholesterolemia and statins

Familial hypercholesterolemia as a model for the way environmental factors working together with single gene mutations modify phenotype

Monogenic genes as genetic risk factors in common disease

REFERENCES

11 Environment and disease

Defining "environment"

Estimations of the health impact of environmental factors

Environment as determinant of (i) genotype and (ii) disease

Non-insulin-dependent (Type II) diabetes mellitus

"Thrifty genes", and selective insulin resistance

Multiple sclerosis

Joint effects of genes and environment

Major Mendelian genes versus minor polygenes as predisposers

Prevention strategies: whole populations, high-risk groups or selected individuals?

Conclusions

REFERENCES

12 Contemporary ethico-legal issues in genetics

Introduction

Legal-ethical issues in research settings

Recruitment for case-control studies

Recruitment for family studies

Feedback for disease prevention

Ownership and governance issues

Summary/conclusion

Issues in clinical research settings

Research involving human subjects

Ethical oversight

Informed consent

Remuneration

Randomized trials

Publication

Research undertaken in the developing world

Summary/conclusion

Legal-ethical issues in clinincal settings

Embryonic screening and selection

Risks of coercion in counseling

Attitudes and approaches to disability

Equality of access and discrimination

Summary/conclusion

Conclusion

REFERENCES

SECTION 2 Common medical disorders

13 Developmental disorders

The medical significance of developmental disorders

Broad etiological groups

Measuring the genetic contribution in developmental disorders

Identifying the multiple epistatic determinants underlying a developmental disorder: Hirschsprung disease

Beyond oligogenic disease

Identification of environmental contribution to developmental disorders

Classic teratogens

Nutritional deficits as teratogenic influences

The intrauterine diabetic environment: an intrauterine teratogenic milieu

Approaches to identifying teratogens

Summary

REFERENCES

14 Genes, environment and cancer

Introduction

Studies to investigate genes and environment

Study design

Environment and high penetrance genes

Investigations of specific cancers

Bowel cancer

Meat, heterocyclic amines and risk

Folate and colorectal cancer

Melanoma

MC1R, coloration and melanoma risk

Conclusions

REFERENCES

15 The polygenic basis of breast cancer

Introduction

Genetic models of breast cancer susceptibility

Implications of the polygenic model

Implications of the recessive model

Public health implications

Disease prevention in those with single disease susceptibility alleles

Disease prevention under the polygenic model

Finding low-penetrance breast cancer alleles

Conclusion

REFERENCES

16 TP53: A master gene in normal and tumor suppression

Introduction

Characteristics

Gene structure

TP53 gene family

P53 protein

Regulation and function

Regulation of expression

Post-translational regulation: signaling of DNA damage

Downstream of p53: cell-cycle control, apoptosis and DNA repair

Role of p53 in normal suppression of proliferation

Why is TP53 so frequently mutated in cancer?

Mutagenesis versus selection

Beyond loss of suppression: gain-of-function effects

Perspectives: p53 and cancer management

REFERENCES

17 Genetics of colorectal cancer

Introduction

Colorectal cancer epidemiology

Genetic susceptibility to colorectal cancer

Familial adenomatous polyposis coli (FAP)

FAP germline mutations

Cellular functions of the APC protein

Modifiers of FAP

Hereditary non-polyposis colorectal cancer (HNPCC) or lynch syndrome

DNA mismatch repair genes

MMR mutation spectrum and genotype–phenotype correlations

Mismatch repair defects in humans and DNA instability in tumors

Molecular mechanisms of colorectal carcinogenesis and defective MMR

Other candidate susceptibility genes involved in HNPCC

Rare dominant disorders

Juvenile Polyposis syndrome (JPS)

Peutz-Jeghers syndrome (PJS)

Cowden disease (CD)

Recessive inheritance

MYH-associated colorectal neoplasia

MYH protein function and interactions

Common genetic variation and susceptibility to colorectal cancer

Non-truncating variants in the APC gene

Cyclin D1 (CCND1)

Methyl tetrahydrofolate reductase (MTHFR)

STK15 (Aurora-A)

Cytochrome P-450

Cell-cycle checkpoint kinase 2 (CHEK2)

Other putative risk alleles

Conclusions

Acknowledgements

REFERENCES

18 Genetics of autoimmune disease

Introduction

Background: genes and environment

HLA: the major genetic locus in autoimmunity

Genetic approaches to defining non-HLA susceptibility genes

Using animal models to understand genetic contributions to autoimmunity

Conclusions

REFERENCES

19 Susceptibility to infectious diseases

Introduction

Historical perspective

Twin studies and adoption studies

Malaria

Mycobacterial disease: tuberculosis

Mycobacterial disease: leprosy

Mycobacterial disease: rare atypical infections

Human immunodeficiency virus and acquired immune deficiency syndrome (HIV and AIDS)

Conclusion

REFERENCES

20 Inflammatory bowel diseases

Introduction

Environmental factors

Genetic factors

Positional cloning of IBD genes

A major breakthrough: identification of the CARD15/NOD2 gene

REFERENCES

21 Genetic anemias

Introduction

Globin genes and their regulation

Alpha globin cluster

Mutations of the Alpha globin genes causing Alpha thalassemia

Alpha thalassemia due to mutations in a trans-acting factor

Beta globin cluster

Mutations of the Beta globin gene causing Beta thalassemia

Beta thalassemia due to mutations in trans-acting factors

Genetic interactions

Alpha Beata thalassemia

Modifying genes

Genotypephenotype relationships

Prevalence

Role of malaria in the selection of hemoglobinopathy alleles

Public health aspects

Future treatment

What lessons can be learnt from the globin gene system for other genetic diseases?

REFERENCES

22 Genetics of chronic disease: obesity

Introduction

Obesity – a major public health threat

Is genetics important in determining susceptibility to human obesity?

Twin studies

Adoption studies

Heritability of intermediate traits

Why look for human obesity genes?

Methodological issues in the hunt for human obesity genes

What measure of adiposity to use?

Obesity as a disease state or adiposity as a continuous variable?

Progress in the identification of human obesity genes

Monogenic disorders leading to human obesity

Prader-Willi syndrome

Albright hereditary osteodystrophy

Fragile X syndrome

Bardet–Biedl syndrome

Novel human monogenic obesity syndromes

Congenital leptin deficiency

Response to leptin therapy

Partial leptin deficiency in heterozygotes

Leptin receptor deficiency

Pro-opiomelanocortin deficiency

Prohormone convertase 1 deficiency

Melanocortin 4 receptor (MC4R) deficiency

Genetics of common obesity

Linkage studies in common obesity

Association studies in common obesity

Gene/environment interaction

Summary

REFERENCES

23 Type 2 diabetes mellitus

Introduction

Type 2 diabetes: the next global epidemic?

Definitions

Impact

The gap between needs and understanding

Genes, environment and the pathogenesis of type 2 diabetes

The case for genes

Heritability of quantitative traits

The case for the environment

The role of early environment

Towards a synthesis

Genes and environment

Progress towards susceptibility gene identification in type 2 diabetes

Lessons from maturity onset diabetes of the young (MODY)

Lessons from other monogenic syndromes

Genome scans for linkage in multifactorial T2D

Candidate genes

Role of genetics in medical care of T2D

REFERENCES

24 Genetics of coronary heart disease

Genetic and environmental contributions to CHD pathogenesis

Evidence for the genetic basis of CHD

Genetics of monogenic and complex dyslipidemias

Monogenic hypercholesterolemias

Autosomal dominant hypercholesterolemias

Autosomal recessive hypercholesterolemias

Monogenic disorders causing impaired reverse cholesterol transport

Oligo/polygenic (complex) genetic hyperlipidemias

Familial combined hyperlipidemia (FCHL)

Type III hyperlipoproteinemia (dysbetalipoproteinemia or broad Beta disease)

Genetics of human coronary heart disease

Genome-wide studies for coronary heart disease

Candidate gene studies for coronary heart disease

Insights from rodent models

Gene targeting studies

Linkage studies

Conclusions

REFERENCES

25 Genetics of hypertension

Introduction

Mendelian forms of hypertension

Glucocorticoid remediable aldosteronism (GRA)

Apparent mineralocorticoid excess (AME)

Hypertension and hypotension due to MR mutations

Liddle's syndrome

Genetics of blood pressure and essential hypertension

Linkage studies

Candidate gene investigations

Intermediate phenotypes

The ACE gene and trait

Steroid 11-hydroxylation and the CYP11B1/B2 locus

Conclusions and perspectives

REFERENCES

26 Obstructive pulmonary disease

Introduction

Asthma

Environmental risk factors for the development of asthma

Genetic risk factors for the development of asthma

Chronic obstructive pulmonary disease (COPD)

Overlap between asthma and smoking-related COPD

Environmental risk factors for the development of COPD: smoking

Other environmental risk factors that may predispose smokers to COPD

Genetic risk factors for the development of COPD

Alpha1-antitrypsin deficiency

Other genetic risk factors for the development of COPD

Conclusions

REFERENCES

27 Skeletal disorders

Introduction

Low bone mass

Osteoporosis

Osteoporosis-pseudoglioma syndrome

Altered homeostasis of bone resorption and bone formation

Paget's disease of bone

Juvenile Paget's disease

Familial expansile osteolysis

Camurati–Engelmann disease

High bone mass

Decreased bone resorption

Autosomal recessive osteopetrosis

Autosomal dominant osteopetrosis

Osteopetrosis with renal tubular acidosis

Pycnodysostosis

Increased bone formation

Van Buchem's disease and sclerosteosis

High bone mass

Craniometaphyseal dysplasia

Chondrocalcinosis

Altered bone homeostasis in inflammatory arthritis

Rheumatoid arthritis

Ankylosing spondylitis

Summary

Glossary

Acknowledgements

REFERENCES

28 The genetics of common skin diseases

Introduction

Spatiotemporal patterns of common skin diseases

Scope of chapter

Psoriasis (OMIM 177900)

Acne (acne vulgaris, OMIM 604324)

Atopic dermatitis (OMIM 603165)

Skin cancers

Human pigmentation

The MC1R and human pigmentation and skin cancer

MC1R and p16

Other genetic factors and skin cancer

Conclusions

REFERENCES

29 Molecular genetics of Alzheimer's disease and other adult-onset dementias

Genetic basis of Alzheimer's disease and Lewy body variant

The amyloid precursor protein

Apolipoprotein E (APOE)

Presenilin 1

Presenilin 2

Other genes for Alzheimer's disease

Familial non-specific dementia

Familial British dementia (FBD) and familial encephalopathy with neuronal dementia with neuroserpin deposits

Fronto-temporal lobe dementia (FTD)

Tau mutations in FTDP-17

Practical implications

Predictive genetic testing

Pharmacogenomics

REFERENCES

30 Major psychiatric disorders in adult life

Clinical features and epidemiology

Genetic epidemiology

Affective disorders

Schizophrenia

Finding genes

Positional candidate genes

Functional candidate genes

Conclusions

REFERENCES

31 Speech and language disorders

Introduction

Epidemiology of speech and language disorders

A rare monogenic speech and language disorder

KE family phenotype

Patient CS

Specific language impairment (SLI)

Evidence for a genetic component to SLI

Clinical measures for SLI

Summary

Autism spectrum disorders

Evidence for a genetic component to autism

Clinical measures for autism

Further observations on autism

Summary

Molecular genetic approaches to speech and language disorders

SPCH1

Identification of the SPCH1 gene – FOXP2

FOXP2 genomic structure and function

Expression studies of FOXP2

Proposed molecular mechanisms

SLI and autism

Genome screens for SLI

Genome screens for autism

Cytogenetic studies for autism

Association studies for autism

Candidate gene investigations for SLI and autism

Discussion

Acknowledgements

Glossary

Clinical terms

Technical terms

Acknowledgements

REFERENCES

32 Common forms of visual handicap

Introduction

Age-related cataract

Glaucoma

Primary open angle glaucoma

Primary angle closure glaucoma

Age-related macular degeneration

Genetic influences in age-related macular degeneration

Extracellular matrix proteins

The innate immune system: complement factor H

Acknowledgements

REFERENCES

33 Genetic and environmental influences on hearing impairment

Prevalence of hearing impairment

Mechanisms of hearing impairment

Treatments

Environmental causes of deafness

Role of genetics in deafness in the population

Genes and environment

Genetic heterogeneity

Modifiers of deafness genes

A model for human hearing impairment?

Acknowledgements

REFERENCES

34 Pharmacogenomics: clinical applications

Introduction

Genes that influence drug response

Clinical applications of pharmacogenetics

Ethnic differences in allele frequencies

Current applications of pharmacogenetics

Future developments

Ethical issues

REFERENCES

Index