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Genes and Common Diseases

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  • 37 b/w illus. 23 colour illus.
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 (ISBN-13: 9780521541008)

Genes and Common Diseases
Cambridge University Press
978-0-521-83339-4 - Genes and Common Diseases - by Alan Wright and Nicholas Hastie
Index

Index

A1555G, aminoglycoside-related hearing loss 510

Abacavir susceptibility 150

Abeta peptide, overexpression in Alzheimer’s disease 127, 128

ACE, and angiotensin converting-enzyme 366–7, 385–6

acetylators, fast and slow 170–1, 218, 520

acne vulgaris 430–1

active chromatin hub (ACH) 11

ADAM-17 440

ADAM-33 394

adiposity, as continuous variable 331–2

admixture mapping 81–2, 99, 101

admixed population 81

adoption studies 456

obesity 329–30

schizophrenia 459

adrenal hyperplasia 143, 149

adrenocorticotrophic hormone, and CYP11B1 379, 386

adverse drug reactions, hospital admissions 516

affective disorders 454–6

genetic epidemiology 455–6

Africa, resistance to malaria 149

African Americans, admixed population 81

aging 132–41

familiality of exceptional longevity 134–6

proposed multifactorial model 136–7

genes predisposing to exceptional longevity 137–9

relative contribution of genes, environment and luck 133

survivors, delayers and escapers (of morbidity) 132–3

aging diseases

age-related cataract 488–93

age-related macular degeneration 489, 496–501

aggregation of protein 124–6

and new life/livestock practices 126

AGT, angiotensinogen 384–5

air pollution, asthma 391

AKT-1, V-AKT murine thymoma viral oncogene homolog-1 463

Albright hereditary osteodystrophy 333

alcoholism, depression spectrum disease 461

aldosterone synthase deficiency 380

aldosteronism

glucocorticoid-remediable aldosteronism, and CYP11B1 379

pseudohypoaldosteronism type-1 380, 382

alleles, identical by descent (IBD) 61

allelic heterogeneity 53, 100

and new disease 53–4

alpha1-antitrypsin deficiency 397–8

alternative splicing 5

Alu sequence 367

Alzheimer’s disease 159–60, 439–45

Abeta peptide overexpression 127, 128

amyloid precursor protein 159–60, 440–1

apolipoprotein E, APOE 153, 172, 441–2, 448

genetic basis and Lewy body variant 439–40

Huntington’s disease counseling model 447–8

other genes 444–5

presenilin-1 and -2 442–4

see also amyloid deposition diseases

amines, heterocyclic, and red meat 170, 217–18

amitryptyline, CYP2D6-dependence, dose recommendations 521

amyloid deposition diseases 118

formation of pathological deposits 121–4

origins 124–6

therapeutic intervention 126–8

amyloid fibrils

protective sequestration mechanism 125

and serum amyloid P 127

structure and mechanism 119–24

amyloid precursor protein and beta-peptide 159–60, 439–41

ancestral susceptibility models 64

anemias 316–27

future treatment 324–5

genetic interactions 321–2

genotype–phenotype relationships 321–2

modifying genes 321

globin genes and their regulation 317–21

prevalence 322–4

malaria, selection of hemoglobinopathy alleles 323–4

public health aspects 324

see also thalassemia

Angelman syndrome 32

angiotensin converting-enzyme, and ACE 366–7, 385–6

angiotensinogen

AGT 384–5

synthesis 378

animal models

autoimmune disease 273–4

cardiovascular risk factors 369–71

CFTR mutations 155

chondrocalcinosis 417

coronary heart disease 368–71

familial adenomatous polyposis coli (FAP) 249–51

hearing impairment 510, 511, 512

inflammatory bowel disease 306

insulin resistance 368–70

MMR 254

obesity 334–5

skin color 433

TP53 deficiency 237–8

see also models

Ank, murine progressive ankylosis 417

ANKH 417

ankylosing spondylitis 142–3, 144, 418–20

antidepressants, CYP2D6-dependent, dose recommendations 521

antimorphs (dominant negative mutations) 35

antioxidants, dietary 392–3

antipsychotics, dopamine D2 receptor 462

APC 152, 248–51

non-truncating variants 257–61

APC protein 248–51

apo A5 365

APOE 160

apolipoprotein E, Alzheimer’s disease 153, 172, 441–2, 448

apparent mineralocorticoid excess 379–81

AQP0 492

arthritis

inflammatory 417–20

rheumatoid 418

spondyloarthritides 418–20

arthrogryposis multiplex congenita 204

assisted reproductive technologies (ARTs) 33

association-based gene mapping 64–72

analysis 69–71

consistency/strength of association 107–8

direct/indirect association 103–5

false discovery rate 71

HapMap project 80, 84–9, 104

multiple testing 71–2

null hypothesis 70

odds ratio (OR) 70

population attributable risk/fraction (PAR) 70, 93–4

power (sample size) 66–7, 95–6

sample collection and population stratification 67–8

SNP selection 68–9

stages 65

vs linkage mapping 73

see also linkage disequilibrium

asthma 391–4

environmental risk factors 173, 391–3

genetic risk factors 173, 391–3

Ataxia Telangiectasia 236

atherosclerosis, animal models 368–71

ATM 230

atopic dermatitis 431–2

atopy 392

ATP-dependent chromatin remodeling 13–14

enzymes 24

ATR-X, alpha-thalassaemia/mental retardation syndrome 26–7

Aurora-A, STK15 259

autism, specific language impairment and autism 471–80

association studies 478

autism spectrum disorders 472–3

clinical measures for autism 472–3

evidence for a genetic component to autism 472

candidate gene investigations 478–82

concordance and prevalence rates 471

cytogenetic cases 478

region of linkage on chromosome-7 479

genome screens for autism 476–8

genome screens for SLI 475–80

loci detected 477

see also speech and language disorders

autoimmune diseases 144–8, 268–76

animal models 273–4

background: genes and environment 268–70

defining non-HLA susceptibility genes 271–3

environmental effects 146

HLA (human leukocyte antigen) 270–1

immunopathology 146

mechanisms for associations 147–8

MHC 144–8

non-MHC genes 146

BACE-1, beta-secretase 440

Bardet–Biedl syndrome 333

Bartter’s syndrome, Gitelman’s variant 380

Beckwith–Wiedemann syndrome 33

beta-globin 10–11

BFSP2 492

‘biobanks’ 101–2

bipolar affective disorder 454–68

birth defects

disruptions, deformations, malformations 202

mortality by age groups 202

Blau syndrome, granulomas 310–11

bone

altered homeostasis

bone resorption/formation 410–13

in inflammatory arthritis 417–20

high bone mass 413–15

autosomal dominant osteopetrosis 413–15

autosomal recessive osteopetrosis 413

decreased bone resorption 413–15

pycnodysostosis 415

increased bone formation 416–17

high bone mass 416–17

juvenile Paget’s disease 411, 412

low bone mass 408–10

genes contributing 409

osteoporosis 408–10

osteoporosis–pseudoglioma syndrome 410

OPG/RANK/RANKL axis 418–19

osteoblasts 406–8

osteoclasts 406–8

Paget’s disease 410–12

remodeling 407

resorption and formation, increased bone turnover 411

bottleneck events 80–1

boundary elements/insulators 10

bowel cancer see colorectal cancer

BRCA mutations 153

breast cancer 225

carrier frequency 213, 216

smoking and cancer risk 217

breast cancer 224–32

finding high-risk individuals 154

finding low penetrance alleles 230–1

models of susceptibility 224–8

polygenic model 225–8

recessive model 228

public health implications 228–30

mammography 229–30

susceptibility alleles 228

under polygenic model 228–30

broad beta disease (hyperlipoproteinemia, type III) 365

bronchitis 394–400

3C-technology 10–11

C1QTNF5 498

CACC box 156

Camurati–Engelmann disease 411, 413

canalization 207

cancer

chemotherapy 521

and DNA methylation 29–30

environmental exposures 213–23

epidermal growth factor receptor (EGFR) 522

epigenetic mechanisms 30–4

CARD15/NOD2 304, 308–11

cardiovascular risk factors

animal models 369–71

BMI 328

HDL and LDL particle sizes 138

hypertension 377–86

and insulin resistance 367–8

carriers, Hardy–Weinberg law 62–3

case-control studies 70, 103

controls, recruitment 177–8, 216

genotype and environment 215–16

vs cohort studies 103

cataract 488–93

catechol-O-methyltransferase, COMT 462

CCNDI, cyclin DI 258

CD32 286

CD36 285

deficiency, insulin resistance 368, 369–70

CD40 285

CD209 281

CDCV hypothesis 53, 64, 75, 98, 153

Cdh23 511

hearing loss 511

CDKN2A carriers, risk of melanoma 215, 216

cell-cycle checkpoint kinase-2, CHEK2 259–60

central dogma 6

centromeric heterochromatin 34

CFH, complement factor H 499–500

CFTR 155

CFTR mutations, animal models 155

CHEK2

1100delc variant 230

cell-cycle checkpoint kinase-2 259–60

chemotherapy, cancer 521

chi-squared contingency table test, null hypothesis 70

cholesterol

familial hypercholesterolemia 360–4

impaired reverse transport 364

cholesterol ester transfer protein 362

deficiency 364

and longevity 138

chondrocalcinosis 414, 417

chromatin 34

active chromatin hub (ACH) 11

active vs inactive 21

model 21

condensation/decondensation 34–5

DNA packaging 11–12, 21

epigenetic modification 20–34

euchromatin 35

loops 16

modification and transcription 11–14

remodeling 11–15, 23–4

status within genome 15

structure 11

chromosomal architecture 4

chromosomal disorders 202–3

chromosome territories 16

chronic obstructive pulmonary disease (COPD) 394–400

candidate genes 399

environmental risk factors 396

smoking-related 394–6

chylomicrons 362

cis-acting regulatory elements 4, 8–10, 35

CJD see Creutzfeldt–Jakob disease

CLCNKB 380

clinical research 182–7

case-control studies 70, 103, 215–16

controls, recruitment 177–8, 216

developing world 187–8

ethical oversight 183–5

ethico-legal issues in genetics 182–8

family studies 178–80

feedback for disease prevention 180–1

informed consent 185–6

instruments 182–3

publication 187

randomized controlled trials 186–7

remuneration 186

risk–benefit analysis 184–5

clusterin 124

coactivator proteins, transcriptional activation 9, 11

coalescent process 49

cochlear implant 508

codons, premature termination 7

cohort studies, genotype and environment 214–15

COL1A1 408

collagens 162

colorectal cancer 245–67

APC 152, 248–51

common genetic variation and susceptibility 257–61

non-truncating variants in APC 257–61

other putative risk alleles 260–1

dietary aspects 217–18, 217–19

epidemiology 245–7

familial adenomatous polyposis coli (FAP) 247–51

folate and 219–20

genetic susceptibility 247

hereditary non-polyposis colorectal cancer (HNPCC) 251–5

MYH protein 256–7

NAT2, fast and slow acetylators 170–1, 218, 520

rare dominant disorders 255–6

recessive inheritance 256–7

smoking 219

common disease–common variant (CDCV) hypothesis 53, 64, 75, 98, 153

complement factor H, CFH 499–500

complex disease

genetic architecture 97–100

models 52–3

trait mapping 92–112

characteristics of populations 100–2

detection of rare variants 99

expression of QTLs 105–6

family-based/population-based approaches 98, 102–5

genetic effect sizes 97–100

heritability estimates 94

preliminary steps 94–7

results 107–9

COMT, catechol-O-methyltransferase 462

congenital adrenal hyperplasia 143, 149

hypertension syndromes 380

congenital heart disease, genes identified 203

coronary heart disease 359–76

environmental contribution 359–60

risk factors 360

evidence for genetic basis 360

genome-wide studies 365–8

incidence 359

monogenic and complex dyslipidemias 361–5

rodent models 368–71

cortisol, and apparent mineralocorticoid excess 379–81

counseling

genetic disease 447–8

legal-ethical issues 190–1

Cowden disease (CD) 255–6

CpG island 26, 35, 253

CpGs, methylated 25–6

craniometaphyseal dysplasia 414, 417

Creutzfeldt–Jakob disease

genes 284

regulation of prion protein by quinacrine 126–7

Crohn’s disease see inflammatory bowel disease

alpha-crystallin, CRY genes 491–2

CTLA4, immunomodulatory co-receptor 147

CX46 and CX50 492

cyclin DI, CCNDI 258

CYP2C, CYP2D, and CYP3A, drug metabolism 519–20

CYP2D6

CYP2D6-dependent antidepressants, dose recommendations 521

ethnic diversity 523

ultrarapid metaboliser 519

CYP11B1

and adrenocorticotrophic hormone 379, 386

congenital adrenal hyperplasia 380

CYP11B1 and CYP11B2 386

glucocorticoid-remediable aldosteronism 379–81

CYP11B2, aldosterone synthase deficiency 379–81

CYP17, congenital adrenal hyperplasia 380

CYP21, and 21-hydroxylase deficiency 149, 380

cystic fibrosis 154–5

Cystic Fibrosis Genotype–Phenotype Consortium 155

cytochrome P-450 259

cytoskeletal proteins 492

DAO (D-amino-acid-oxidase), G72 461–2

DC-SIGN 281, 287

deafness, GJB2 509

deformations and malformations 202

dementia

familial British dementia (FBD) 445

familial encephalopathy, neuronal dementia with neuroserpin deposits 445

familial non-specific dementia 445

fronto-temporal lobe dementia (FTD) 445–6

non-specific dementia 445

pharmacogenomics 448–9

predictive genetic testing 447–8

tau mutations in FTDP-17 446–7

see also Alzheimer’s disease

dengue virus, associated genes 284

depression

antidepressants, CYP2D6-dependent, dose recommendations 521

and MTHFR 460–1

unipolar/bipolar 454–6

twin studies 455

depression spectrum disease, and alcoholism 461

‘detectance’ 94

improving 95

developing world, clinical research 187–8

developmental disorders 201–12

environmental contribution 204, 207–9

etiological groups 202–4

genetic contribution 204–7

mortality by age groups 202

prevalence 201–2

diabetes mellitus type-1

HLA-DQ allele 144, 145, 270–1

pregnancy

structural malformations 208

vitamins 209

diabetes mellitus type-2 344–58

and BMI 328

candidate genes 351–3

definitions 344

environmental factors 167–8, 346–8

genes 345–6, 348

heritability of quantitative traits 346

medical care 353

and metabolic syndrome 367–8

next global epidemic 344–5

susceptibility gene identification 348–51

genome scans for linkage in multifactorial T2D 350–1

maturity onset diabetes of the young (MODY) 348–50

other monogenic syndromes 350

thrifty genes and selective insulin resistance 167–8

diet

antioxidants 392–3, 397

and asthma 392

and colorectal cancer 217–19

red meat, heterocyclic amines 170, 217–18

and respiratory function 397

disability

legal-ethical issues 191–3

postponement in aged people 132

disability-adjusted life-years (DALYs) 278

DISC1 and DISC2 462

disruptions, deformations, malformations 202

DNA deletions, disorders 203

DNA methylation 15, 35

and cancer 29–30, 219

transcriptional repression 25–6

see also folate

DNA mismatch repair genes 251–4

DNA instability in tumors 253

DNA modification 24–5

dominant negative mutations 35

dopamine receptor, DRD3 462–3

DRD3, dopamine receptor 462–3

Drosophila, DSCAM 6

drug responses see pharmacogenomics

DTNBP1, dysbindin 461

Duffy antigen/chemokine receptor 285

dysbetalipoproteinemia 365

dysbindin, DTNBP1 461

dyslipidemia, animal models 368–71

embryonic screening, and selection, legal-ethical 189–90

emphysema 394–400

and alpha1-antitrypsin deficiency 397–8

ENaC, epithelial sodium channel 382–3

encephalopathies, transmissible, aggregation of protein 124

endophenotypes 97

endoplasmic reticulum, protein folding 116

endosteosis, Van Buchem’s disease 414, 416

enhancer elements 9, 10–11, 35

environment 164–75

definitions and scope 164–5

as determinant of genotype and disease 166–7

estimations of health impact 165–6

gene–environment interactions 170–1

major mendelian genes vs minor polygenes as predisposers 171–2

prevention strategies: whole populations, high-risk groups or selected individuals 172–3

environmental exposures

autoimmune diseases 146

and cancer 213–23

developmental disorders 204, 207–9

epidermal growth factor receptor (EGFR), cancer 522, 523

epigenetic mechanisms 14–15, 20–34

in cancer 30–4

defined 14, 20, 35

malformations 203

epistasis, gene–gene interactions 106

epithelial sodium channel, ENaC 382–3

equality of access, and discrimination 193–4

ERBB2, tyrosin receptor 522

ethico-legal issues in genetics 176–98

clinical research settings 182–8

ethical oversight in clinical research 183–5

feedback for disease prevention 180–1

legal-ethical issues in clinical settings 188–94

attitudes and approaches to disability 191–3

embryonic screening (PGD) and selection 189–90

equality of access and discrimination 193–4

risks of coercion in counseling 190–1

legal-ethical issues in research settings 176–7

ownership and governance issues 181–2

pharmacogenomics 526

recruitment for case-control studies 177–8

recruitment for family studies 178–80

Ewens sampling theory 48–9

exonic splicing enhancers 157–9

exons 4, 6

alternative 6

expected likelihood of odds (eLOD) score 76

expression quantitative trait loci (eQTLs) 105–6

expressivity, single gene disorders 153–5

‘extended haplotype homozygosity’ (EHH) 84, 89

extracellular matrix (ECM) proteins 497

extreme discordant and concordant (EDAC) sampling 75, 102

eye diseases 488–504

Factor VII 367

familial adenomatous polyposis coli (FAP) 247–51

animal models 249–51

cellular functions of APC protein 248–9

FAP germline mutations 248

FAP modifiers 249–51

familial British dementia (FBD) 445

familial combined hyperlipidemia (FCHL) 364–5

familial defective apolipoprotein B-100 (FDB) 361–4

familial encephalopathy, with neuronal dementia and neuroserpin deposits 445

familial expansile osteolysis 411–13

familial hypercholesterolemia 360–4

frequency 360

mortality 161

model modification of phenotype 161

and statins 160–1

familial non-specific dementia 445

family studies

clinical research 178–80

major design and size constraints 216–17

FEN1B 445

fetal neuromuscular proteins, arthrogryposis multiplex congenita 204

fibulin1-6 497

fitness, defined 49

FLAP, and 5-lipoxygenase activating protein 366

folate deficiency

and colorectal cancer 219–20

and neural tube defects (NTDs) 207–8

founder populations, inbred 101

FOXC1 158

FOXP2 469

genomic structure and function 474

fragile X syndrome 333

fronto-temporal lobe dementia (FTD) 445–6

FSHD 158

FST statistic 89

G protein signalling-4, RGS4 462

G6PD 285

G72, DAO (D-amino-acid-oxidase) 461–2

gain-of-function, atherosclerosis, animal models 369, 370

galectin-2, and myocardial infarction 367

GALK1 492

Gardner’s syndrome 248

GCD 349

gefitinib 522

gene deletion syndromes 203

gene expression 6–19

gene mapping 59–79

association-based gene mapping 64–72

future prospects and impact on health 76–7

homozygosity mapping 63

linkage mapping in families 60–4

null hypothesis 70

quantitative trait loci (QTLs) 54–5, 72–5

gene silencing (transcriptional repression) 37

gene therapy, TP53 deficiency 241

genes

defined 3

number of human genes 5, 20

number of proteins 5

silenced 11

genetic counseling 190–1, 447–8

genetic diagnosis, preimplantation (PGD) 189–94

genetic disease, incidence 45

genetic drift 46–8

genetic testing

permutation testing 71–2

pharmacogenomics 448–9

predictive genetic testing 447–8

genetic variation

classification 108

population, measurement 45–6

see also single nucleotide polymorphisms (SNPs)

genomic disorders 203

genomic imprinting 35

and ARTs 33–4

diseases of 31–4

model 32

genotype relative risk (GRR) 67, 75

Gitelman’s variant, Bartter’s syndrome 380

GJB2, deafness 509

glaucoma 493–6

primary angle closure 495–6

primary open angle 493–5

GLC1A-G 494

GLI3 158

globin genes and their regulation 317–21

alpha globin cluster 317–18

alpha thalassemia 318–19

mutations in trans-acting factor 319

beta globin cluster 318, 319

glucocorticoid-remediable aldosteronism, CYP11B1 and CYP11B2 379–81

glucokinase 349

glucose-6-phosphate dehydrogenase, G6PD 285

glutamate receptor metabotropic-3, GRM3 463

glutathione-S-transferase 399, 521

glycophorin C 285

Gordon’s syndrome, pseudohypoaldosteronism type-1 380, 382

granulomas, Blau syndrome 310–11

GRM3, glutamate receptor metabotropic-3 463

growth control, SWI/SNF complex 24

HapMap project

association-based gene mapping 80, 84–9, 104

fine localization 88–9

identifying evidence for selection 89

SCN8a dataset 86–8

tagging SNPs 84–6

haptoglobin 284

Hardy–Weinberg law 46–8

carriers 62–3

HBA 158

HBB 158

HDL cholesterol, in premature CHD 364

HDL lipoproteins, metabolism 362

hearing impairment 505–27

age-related 509–11

aminoglycoside-related 510

environmental causes, aminoglycoside-related 510

genetic heterogeneity 511

mechanisms 505–7

mendelian disorders 511

prostheses 507–8

heart disease

genes identified in congenital syndromes 203

see also myocardial infarction

heat shock proteins (molecular chaperones) 113–15

Helicobacter pylori, associated genes 283

heme-oxygenase-1, HMOX-1 398–9

hemochromatosis 143, 149

hemoglobin

HbF 321

structure 316

hemoglobinopathies

geographical distribution 322

and malaria 323–4

public health aspects 324

hemolytic anemia 285

hepatitis virus B and C, associated genes 284

hepatocyte nuclear factors

1-beta 349

4-alpha 349

hereditary non-polyposis colorectal cancer (HNPCC: Lynch syndrome) 154, 251–5

DNA mismatch repair genes 251–4

MMR defects and DNA instability in tumors 253

MMR mutation spectrum and genotype-phenotype correlations 252–3

molecular mechanisms of colorectal carcinogenesis and defective MMR 253–4

other candidate susceptibility genes 254–5

heritability estimates, trait mapping 94

heterochromatin 11, 21, 35

centromeric 34

heterochromatin protein-1 (HP1) (nuclear factor) 22–3

heterozygosity, genetic markers 61

hexokinase-4 349

Hirschsprung disease 205–6

sibling recurrence risk 205

histone acetyltransferases (HATs) 12–13, 22, 31

histone deacetylases (HDACs) 22–4

histone methyltransferases (HMTs) 23

histones 11, 21

histone code 14

modification 22–3

HIV infection and AIDS 290–1

genes 283–4

and MHC system 148–9

HLA (human leukocyte antigen) 270–1, 279

HLA-B27 418–20

rheumatoid arthritis 418

tuberculosis 287

see also MHC

HMG proteins 11

HMOX-1, heme-oxygenase-1 398

HNF1A 349

HNF4A 349

homozygosity mapping 63

hormone replacement therapy, and colorectal cancer 245

hospital admissions, adverse drug reactions 516

Hoxd complex 158

HP1, heterochromatin protein-1 22–3

HSD11B2, 11-beta hydroxysteroid dehydrogenase type-2 381

HSF4 492

5-HT2A, serotonin receptor 462–3

Human Genome Project, media claims xviii–xiv

human subjects research see clinical research

human Toll-like receptors 272, 279–81

reported ligands 280

Huntington’s disease 154

counseling 447–8

11-beta hydroxylase

CYP11B1, glucocorticoid-remediable aldosteronism 379

deficiency, and CAH 380

17-alpha-hydroxylase

deficiency, and CAH 380

hypercholesterolemia 364

21-hydroxylase deficiency, and CYP21 149, 380

11-beta hydroxysteroid dehydrogenase type-2, HSD11B2 381

hygiene hypothesis 392

hypercholesterolemia, monogenic disorders 360–4

hyperlipidemia, familial combined (FCHL) 364–5

hyperlipoproteinemia, type III 365

hypertension 377–90

defined 377

HyperGen study 384

intermediate phenotypes 385–6

linkage studies 383–5

mendelian forms 378–83

undertreatment 377

hypertension and hypokalemic alkalosis syndrome 381

hypokalemic alkalosis syndrome 381

ICAM Kilifi 285

identical by descent (IBD) alleles 61, 74

IFNAR1, interferon-alpha receptor-1 286, 289

infectious diseases 277–301

deaths (1999) 278

disability-adjusted life-years (DALYs) 278

historical perspective 277–8

human Toll-like receptors, reported ligands 280

and immature immune system 146

malaria 281–6

MHC 148–9

mycobacterial disease 286–9

Pseudomonas infections 149

reportedly associated genes 282–4

twin and adoption studies 278–81

infertility, CF patients 155

inflammatory arthritis 417–20

inflammatory bowel disease 302–15

animal models developing a colitis 306

Crohn’s, and NOD2 53, 75

environmental factors 303–4

gut flora hypothesis 304

genetic factors 305–11

and NOD2 53, 75

positional cloning of IBD genes 307–8

functional candidate genes investigated in IBD 307

localization of IBD loci 308

twin studies from Sweden and Denmark 306

informed consent 185–6

inositol-5-phosphatase, SHIP2 385

insulators 10

insulin degrading enzyme 440

insulin promotor factor-1 349

insulin recptor, mutations 350

insulin resistance

CD36 deficiency 368, 369–70

and CV risk factors 367–8

selective, diabetes mellitus type-2 167–8

insulin-like growth factor-1 260

interferon-alpha receptor-1, IFNAR1 286, 289

interferon-gamma 288

international collaboration 109

introns 4

IPF1 349

Iressa 521

iris, congenital absence, PAX6 157

juvenile polyposis syndrome (JPS) 255

KIR, MHC-associated disease 147

LCT 158

LDL cholesterol, hypercholesterolemia 160–1, 363

LDL receptor

animal models 369

and CHD risk 153

LRP5 408

LRP5 mutations, familial hypercholesterolemia 361

leishmaniasis 282, 287

LEKT1 394

leprosy 288–9

associated genes 283

leptin, reponse to leptin therapy 335

leptin deficiency 334–5

partial, in heterozygotes 335

leptin receptor deficiency 335–6

leukotriene A4 hydrolase, and myocardial infarction 367

Lewy bodies 121

Liddle’s syndrome 380, 382–3

LIM2 492

linkage disequilibrium 51–2, 59–60

admixture mapping 81–2

‘blocks’ 83

estimation of LD 66

genome-wide patterning 80–1

localized LD 82–9

and recombination 82–3

selection and shaping 83–5

MALD method 82

shared IBDs 104

signal of selection 8

see also association

linkage mapping

in families 60–4

power requirements 102

required no. of sibling pairs to detect 74

transmission disequilibrium test (TDT) 72

vs association-based gene mapping 73

linkage regions 63

5-lipoxygenase activating protein, and FLAP 366

lipoproteins, metabolism 362

locus control regions 9–10, 157

Log of odds (LOD) score 63, 73, 76–7

expected (ELOD) 76

long distance regulators 156–7

longevity studies 132–41

loss-of-function, atherosclerosis, animal models 369, 370

LRP5

LDL receptor 408, 416

mutations, familial hypercholesterolemia 361

lung disease, environmental risk factors 396

lymphotoxin-alpha 367

lysine histone acetyltransferases (HATs) 22

lysine histone methyltransferases (HMTs) 23

lysozyme, and aging diseases 126

macular degeneration 489, 496–501

MAF 158, 492

malaria 281–6

associated genes 282

and hemoglobinopathies 323–4

resistance 149, 285–6

sickle-cell trait and disease 281, 323

susceptibility, MHC 286

and thalassemia 317

MALD method, linkage disequilibrium 82

malformations 202

mammography 229–30

maternally inherited diabetes and deafness (MIDD) 350

matrix attachment sites (MARs) 10

maturity onset diabetes of the young (MODY) 348–50

MC1R

and p16, human pigmentation 435

and skin cancer 432–4

skin color and melanoma risk 220–1, 433

MC4R, melanocortin 4 receptor 337

MDM2 236

MED1 253

melanin 220–1, 432–3

pheomelanin 221, 432–3

melanocortin 4 receptor, MC4R deficiency 337

melanoma risk

in CDKN2A carriers 215, 216

skin color 220

MC1R 220–1

MELAS syndrome 350

membrane transport proteins 492

membranoproliferative glomerulonephritis, CFH mutations 500

mendelian randomization 106–7

mental retardation (ATR-X syndrome) 26–7

MEOX1 416

metabolic syndrome 367

metabonomics 518

methyl tetrahydrofolate reductase, MTHFR 258–9, 409

methylated CpGs 25–6

methyl-CpG binding protein (MeCP2) 27–8, 30

methylenetetrahydrofolate reductase, C677T variant 219

MHC 142–51

Abacavir susceptibility 150

autoimmune diseases 144–8

features/general considerations 142–4

infectious diseases 144, 148–9

malaria susceptibility 286

Pseudomonas infections 149

linkage disequilibrium across region 144

psoriasis 149–50

TAP transporters 149

microarray analysis 35–6

microbial burden, reduction, and immature immune system 146

microsatellite instability 219, 253

microsatellite markers 61

microsomal epoxide hydrolase, mEPHX 399

mineralocorticoid receptor (MR) 382

mismatch repair genes 251–4

mutations 252

mismatch repair proteins, hMSH2 and hMLH1 220

mitochondrial genome, A1555G, and aminoglycoside-related hearing loss 510

MLH1, MLH3 251–3

models

active vs inactive chromatin 21

ancestral susceptibility 64

complex disease 52–3

genomic imprinting 32

multi-locus 51–2

single-locus natural selection 49–51

Wright–Fisher model 47

see also animal models

modifier loci 155–6

molecular chaperones

clusterin 124

functions 125

protein folding 113–15

molecular mimicry hypothesis, T cells 147

Mormon families, linkage in schizophrenia 460

mRNAs

from single gene 5

structure variations 5–6

MSH6 251–2

MTHFR

and depression 460–1

methyl tetrahydrofolate reductase 258–9, 409

Muckle–Wells syndrome, PYPAF1 311

multiple sclerosis 168–70

ultra-violet radiation (UVR) 169

murine thymoma viral oncogene homolog-1, V-AKT 463

mutation–selection balance 50

mutations

de novo, newborns 45

dominant negative 35

genomic mutation rate 45

incidence, Mendelian 46

rates, new mutations 60

mycobacterial disease 286–9

associated genes 283

leprosy 288–9

rare atypical infections 289

tuberculosis 286–8

myeloid/lymphoid or mixed lineage leukemia 31

MYH protein

-associated colorectal neoplasia 256–7

function and interactions 256–7

MYO7A, Usher syndrome 511

myocardial infarction

ACE 385

and galectin-2 367

and leukotriene A4 hydrolase 367

myocilin, MYOC 494–5

N-acetyl transferase 218, 520

NAT2, fast and slow acetylators 520

colorectal cancer 170–1, 218

natural resistance-associated macrophage protein gene, NRAMP1 287

natural selection, model 49–51

neonatal jaundice 285

neprilysin 440

Netherton’s syndrome, SPINK5 394, 431–2

neural tube defects (NTDs), and folic acid 207–8

neuregulin-1, NRG-1 461

NEUROD1 349

neurogenic differentiation-1 349

neuronal dementia, with neuroserpin deposits 445

neutral apoptosis-regulated convertase-1 (NARC-1) 361–2

nicastrin 443

NICD, Notch intracellular domain 443

nitric acid synthase 2A, NOS2A 286

NOD and NOD2 53, 75, 272

Crohn’s disease 53, 75

nonsense-mediated RNA decay (NMD) 7

Norwalk virus, associated genes 284

NOS2A 286

Notch intracellular domain, NICD 443

NRAMP1 287

NSAIDS, and colorectal cancer 246

nuclear compartmentalization 15–16

nuclear factor

heterochromatin protein-1 (HP1) 22–3

kappa B, RANKL 406, 410–12, 418

nuclear matrix 36

nucleolus 16

nucleosomes 21, 22, 36

null hypothesis, chi-squared contingency table test 70

number needed to screen (NNS) 228

number needed to treat (NNT), risk analysis 228

nutritional defects, teratogenesis 207–8

obesity 328–43

adiposity measurement 331

adoption studies 329–30

animal models 334–5

common obesity

association studies 339

linkage studies 337–9

determining susceptibility 329–31

gene/environment interaction 169–70, 339–40

heritability of intermediate traits 330

maternal, as risk factor for disease 209

methodological issues 331

monogenic disorders leading to human obesity 332

neuronal pathwayays involved in regulation of body weight 334

novel human monogenic obesity syndromes 334

progress in identification of human obesity genes 332–9

reponse to leptin therapy 335

threat to public health 328–9

twin studies 329, 330

obstructive pulmonary disease 391–405

candidate genes 399

environmental risk factors 396

smoking-related 394–6

odds ratio (OR), association-based gene mapping 70

OPG/RANK/RANKL axis, bone destruction 418–19

ophthalmic diseases 488–93

optineurin 495

osteoblasts 406–8

osteoclasts 406–8

osteolysis, familial expansile 411, 412–13

osteopetrosis

autosomal dominant 413–15

autosomal recessive 413–14

with renal tubular acidosis 414–15

osteoporosis 408–10

osteoporosis–pseudoglioma syndrome 410

P2X7 purinergic receptor 287

p16, human pigmentation 435

p53

cell-cycle control, apoptosis and DNA repair 236–7

DeltaNp53 isoform 237

effectors of p53 functions 238

negative regulation 237

normal suppression of proliferation 237–9

structure 235

p53 and cancer 233, 240–2

experimental therapy using p53 as target 241–2

p53 in normal suppression of proliferation 237–9

see also TP53

p53/Mdm2 236

P450, and CYP3A4 519–20

Paget’s disease of bone 410–12

PAIRED box 5

parasitic elements 36

parathyroid hormone receptor type-1, PTHR1 410

PASG 27

pathogen-associated molecular patterns (PAMPs) 279

PAX6 158

iris, congenital absence 157

transcription factor, alternative splicing 5

PCR, real time 36

PCSK9, hypercholesterolemia 361–2

PEN-2 443

penetrance, single gene disorders 153–5

peptides and proteins, aggregation rates, effect of mutations 122

peptidylprolyl isomerases 115

permutation testing 71–2

Peutz–Jeghers syndrome (PJS) 255

pharmacogenomics 516–27

clinical applications 520–2

current applications 524–5

CYP3A, CYP2D, CYP2C families 519–20

databases 517

defined 516

ethico-legal issues 526

ethnic differences 522–3

future 525

genetic testing 448–9

metabonomics 518

phenotype informativeness, improving ‘detectance’ 94–5

phenotype–genotype relationships 96

pheomelanins 221, 432–3

phylogenetic footprinting 17

PITX2 158

PITX3 492

plasminogen activator inhibitor-1 368

Plasmodium spp. 282

resistance loci 286

polyadenylation sites 5

polypeptides, synthesis on ribosome 123

population attributable risks/fractions (PAR) 70, 93–4

population genetics 44–58

admixture mapping 81–2

experimental results 54–5

genetic drift 46–8

Hardy–Weinberg law 46–8

measurement of variation 45–6

suitability of populations 100–1

position effect variegation 22, 36

POU3F4 158

power (sample size), association-based gene mapping 66–7, 95–6

Prader–Willi syndrome 32–3, 332–3

preaxial polydactyly (PPD) 157

predictive genetic testing 447–8

preimplantation genetic diagnosis (PGD) 189–94

premature termination codons (PTCs) 7

presenilin-1, PS1 442–3

presenilin-2, PS2 443–4

prion diseases 277

genes 284

prion protein, regulation by quinacrine 126–7

pro-opiomelanocortin deficiency 336

progesterone-sensitive hypertension 380

prohormone convertase 1 deficiency 336–7

Proliferation-associated SNF2-like gene (PASG) 27

proline dehydrogenase, PRODH 462

promotor region, hypermethylation, RB 30

promotors 36

and transcription machinery 7–8

protein aggregation, transmissible encephalopathies 124

protein disulphide isomerases 115

protein folding

catalysts 115

molecular chaperones 113–15

protein misfolding 116–17

diseases 117–18

proteome 4–6

PS1, presenilin-1 442–4

PS2, presenilin-2 443–4

pseudohypoaldosteronism type-1 380, 382

Pseudomonas infections, and MHC 149

psoriasis 149–50, 429–30

psychiatric disorders 454–68

adoption studies 459

genetic epidemiology 455–6

linkage analysis 458–60

positional/functional candidate genes 461–3

PTCs, premature termination codons 7

PTEN

breast cancer 225

Cowden disease 255–6

juvenile polyposis 255

PTHR1 410

pycnodysostosis 414–15

PYPAF1, Muckle–Wells syndrome 311

quantitative trait loci (QTLs) 54–5, 72–5

expression 105–6

linkage mapping 337–8

linkage mapping vs association approaches 73

quantitative traits, complex disease 97

quinacrine, regulation of prion protein 126–7

randomized controlled trials 186–7

RANKL, nuclear factor kappa B 406, 410–12, 418

recombination, and linkage disequilibrium 51–2

red meat, heterocyclic amines 217–18

regulated unproductive splicing and translation (RUST) 7

renal tubular acidosis 415

renin–angiotensin–aldosterone system 378–9

replication timing 36

repressors 9

research in complex disease 92–112

respiratory syncytial virus, associated genes 284

restriction enzymes 36

RET, Hirschsprung disease 205–6

retinitis pigmentosa 153

retinoblastoma gene, promotor region hypermethylation 30

Rett syndrome 27–9

RGS4, G protein signalling-4 462

rheumatoid arthritis 417–18

ribosome, synthesis of polypeptide chain 123

risk analysis

genotype and environment 214–15

number needed to screen (NNS) 228

number needed to treat (NNT) 228

susceptibility genes 228–30

risk profiles 229

risk–benefit analysis, clinical research 184–5

RNA, micro-RNA 159

RNA polymerases (RNAPs) 6–7, 8

RNA Pol II 36

RNA splicing 4

RNA-TRAP 10

RNAi (interference) 36–7

rodent models see animal models

Salmonella typhi, associated genes 283

salt and water balance, renin–angiotensin–aldosterone system 378–9

sampling

Ewens theory 48–9

extremely discordant and concordant (EDAC) 75

increasing sample size 104

power, association-based gene mapping 66–7, 95–6

scaffold attachment sites 10

schistosomiasis 282

schizophrenia 454–61

adoption data 459

functional candidate genes 462–3

linkage analysis 458–9

positional candidate genes 461–2

sib-pair analysis 458

twin studies 457

sclerosteosis, and Van Buchem’s disease 416

sclerostin, SOST 416

SCN8a dataset, HapMap project 86–8

beta-secretase, BACE-1 440

seeding phenomena, transmissible encephalopathies 124

sepsis/septic shock, associated genes 283

serotonin receptor, 5-HT2A 462

serpin deposits 445

Seventh Day Adventists, health and life expectancy 133

SHFM1 158

SHH 157, 158

SHIP2, inositol-5-phosphatase 385

sib-pair analysis 458

sibling risk ratio (lambda-s) 143, 398

sickle-cell trait and disease, malaria 281, 323

signal of selection, linkage disequilibrium 8

single gene disorders 152–63

estimated number 152

genetic risk factors 161–2

genome sequence pinpoints novel potential regulatory variants 159

identifying modifier loci 155–6

locus and allelic heterogeneity 153

mutational spectra 156–9

genome sequence, potential regulatory variants 159

long distance regulators 156–7

new mutation target: exonic splicing enhancers 157–9

plethora of functional mutations 159

position-effect genes in human diseases 158

novel therapeutic approaches 159–60

penetrance, expressivity and genetic modifiers 153–5

single nucleotide polymorphisms (SNPs) 59–60

case–control studies 70

haplotype tagging SNPs 83, 84

HapMap project 80, 84–9

markers for linkage 64

selection, association-based gene mapping 68–9

tSNP design 86–8

siRNA (small interference RNA) 37

sitosterolemia 363, 364

SIX3 158

skeletal disorders 406–26

altered bone homeostasis 417–20

altered homeostasis of bone resorption and bone formation 410–13

bone remodeling 407

high bone mass 413–15

increased bone formation 416–17

low bone mass 408–10

skin cancers 432–5

human pigmentation 432–5

MC1R and p16 435

melanoma risk

CDKN2A carriers 215, 216

skin color, MC1R 220–1

skin color

animal models 433

constitutive/facultative 433

melanoma risk 220–1

skin diseases 427–38

acne (acne vulgaris) 430–1

atopic dermatitis 431–2

psoriasis 429–30

spatiotemporal patterns of common skin diseases 428

SMAD, TGFbeta/SMAD pathway 254–5

smoking

cancer risk 173, 217–18

BRCA mutations 217

chronic obstructive pulmonary disease (COPD) 394–6, 396–9

colorectal cancer 219

pack years, defined 395

sonic hedgehog (SHH) 157

Sorsby fundus dystrophy 499

SOST, sclerostin 416

SOX9 158

SPCH1 locus

SPCH1FOXP2 473–4

specific language impairment 473–4

speech and language disorders 469–87

epidemiology 469–73

glossary 482–3

clinical terms 482–3

technical terms 483

molecular genetic approaches 473–82

expression studies of FOXP2 474–5

identification of SPCH1FOXP2 473–4

proposed molecular mechanisms 475

monogenic speech and language disorder 470

KE family phenotype/pedigree 470

patient CS 470

specific language impairment

and autism 471–80

autism spectrum disorders 472–3

clinical measures for SLI 472

evidence fora genetic component to SLI 471–2

genome screens for SLI 475–80

SPCH1 473–4

see also autism, specific language impairment

SPINK5, Netherton’s syndrome 394, 431–2

spondyloarthritides 418–20

SRY 158

statins, and familial hypercholesterolemia 160–1

STK15, Aurora-A 259

surfactant protein A 288

SWI/SNF complex, growth control 24

alpha-synuclein 127

T cells

MHC class I peptide presentation 142

molecular mimicry hypothesis 147

shaping, and microbial burden reduction 146

TACE 440

TATA-binding protein 8

tau mutations in FTDP-17 446–7

teratogenesis 204, 207–9

in maternal diabetes mellitus type 1 208

nutritional defects 207–8

TGFB1 407, 413

alpha-thalassemia/mental retardation syndrome (ATR-X) 26–7

thalassemia 156, 317, 318–21

alpha thalassemia

mutations of alpha globin 318–19

mutations in trans-acting factor 319

alphabeta thalassemia 321

beta thalassemia

mutations in beta globin 156, 320

mutations in trans-acting factors 320–1

geographical distribution 322

long distance regulators 156–7

and malaria 317

public health aspects 324

thalidomide 207

thrifty genes, and selective insulin resistance 167–8

thrifty phenotype hypothesis 347

TIMP-3 498

TNFRSF1B, tumor necrosis factor receptor family 1B 409

TNFRSF11A 412

Toll-like receptors 272, 279–81

reported ligands and selected references 280

TP53 233–44

breast cancer 225

characteristics 233–5

deficiency, gene therapy 241

frequency of mutations in cancer 239–40

beyond loss of suppression: gain-of-function effects 240

detection of mutations 241

mutagenesis vs selection 239–40

gene structure 234

master gene in normal and tumor suppression 233–44

p53 and cancer 235, 240–2

regulation and function 236–9

regulation of suppression 236

TP53 family 233–5

see also p53 and cancer

TP63 234

TP73 234

trans-acting transcription factors 4, 35

transcription 6–7

termination 7

transcription factors 7–9, 492

general (GTFs) 7–8

trans-acting 4, 35

transcriptional activation 9, 11

coactivator proteins 9, 11

transcriptional regulation 7–15

boundary elements/insulators 10

and chromatin remodeling 11–15

cis-regulatory elements 4, 8–10

and disease 16–17

enhancer action 8–9, 10–11

promotors and transcription machinery 7–8

RNA polymerases (RNAPs) 8

transcriptional repression 37

by DNA methylation 25–6

transcriptome 4–6

transforming growth factor

TGFbeta/SMAD pathway 254–5

TGFbeta1 407, 413

transmissible encephalopathies

aggregation of protein 124

seeding phenomena 124

transmission disequilibrium test (TDT) 72, 102, 143

transposons 37

transthyretin, in amyloid disease 126

trichothiodystrophy 320

trisomies 203

tuberculosis 282, 286–8

associated genes 282, 287–8

and vitamin D 287

tumor necrosis factor alpha 286, 399

tumor necrosis factor receptor family 1B, TNFRSF1B 409

twin studies

and adoption studies, infectious diseases 278–81

asthma 173

atopic dermatitis 431–2

depression (UPD and BPD) 455

inflammatory bowel disease 306

obesity 329, 330

schizophrenia 457

sibling risk ratio 143

TWIST 158

two-hybrid screening 37

typhoid, associated genes 283

tyrosine kinase receptor, ERBB2 522

ubiquitin–proteasome system 124

UDP-glucuronyl transferase 1A1 521

ulcerative colitis see inflammatory bowel disease

ultra-violet radiation (UVR) 169

and MS 169

ultrarapid metaboliser, and CYP2D6 519

unipolar depression 454–68

Usher syndrome, MYO7A 511

V-AKT murine thymoma viral oncogene homolog-1, AKT-1 463

Van Buchem’s disease, and sclerosteosis 414, 416

vas deferens, congenital bilateral absence (CBAVD) 155

vascular endothelial growth factor (VEGF) 498–9

velocardiofacial syndrome, and schizophrenia 462

visual handicap 488–504

age-related cataract 488–93

age-related macular degeneration 489, 496–501

glaucoma 493–6

vitamin D

deficiency 169

and tuberculosis 287

vitamins, antioxidants 392–3

VLDL lipoproteins 362

beta VLDL 365

Wright–Fisher model 47

Xenopus laevis, xMeCP2 target gene 29

xeroderma pigmentosum 435

yeast two-hybrid screen 37


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