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Human Molecular Genetics IV. Genetics of common diseases/ Multifactorial genetics. genetics of common diseases. coronary heart disease (CHD) atherosclerosis, hypertension cancer obesitas diabetes asthma schizophrenia dementia. genetics of common diseases. rarely monogenic

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Human Molecular Genetics

IV. Genetics of common diseases/

Multifactorial genetics

genetics of common diseases
  • coronary heart disease (CHD)
  • atherosclerosis, hypertension
  • cancer
  • obesitas
  • diabetes
  • asthma
  • schizophrenia
  • dementia
genetics of common diseases
  • rarely monogenic
  • most often (i) polygenic and (ii) multifactorial
  • a phenotypic trait determined by
    • (i) interaction between several genes/loci,
    • each with a small additive effect
    • (ii) influence of environmental factors
Genetics of ‘common diseases’

multifactorial inheritance

  • continuous:
  • no specific phenotype eg. length
  • discontinuous:
    • specific phenotype eg diabetes,CL/CP
  • critical balans, treshhold: when crossed, the
  • phenotype appears, severity phenotype



affected dividuals

displaced liability curve for first-degree relatives



affected dividuals

low but increased risk for family members of affected persons

general population risk for more distant relatives

consequence: one or very few affected persons in a family precludes classical

pedigree analysis for Mendelian traits

Genetics of ‘common diseases’

multifactorial inheritance (discontinuous)

general population liability curve



affected dividuals

Genetics of ‘common diseases’

Evidence for multifactorial inheritence

  • family studies
  • increased incidence of a disease in particular families
  • ‘common environment’: check not related individuals (spouses)
  • twin concordance studies
  • dizygous (DZ) vs monozygous (MZ) twins
  • ‘common environment’: twins raised in different environment
  • concordant: both affected or neither affected
  • genetically determined: MZ similarly affected, DZ not
  • environmental: MZ=DZ
  • adoption studies, population and immigration studies
Genetics of ‘common diseases’

Evidence for multifactorial inheritence

Sufficient evidence is obtained for genetic

susceptibility for a given common disorder

Which strategies for disease gene identification

can be followed?

Example of CHD:

what causes do we know for the disease?

Genetics of ‘common diseases’

Identification of genes involved in common diseases

  • methods:
    • linkage analysis using whole genome scans
  • association studies using SNPs
  • candidate gene analysis
  • biochemical analysis
  • combined approach
  • study material:
  • families/affected sibs – family members
  • numbers/selection/clinical diagnosis/pheno-
  • copies/…
  • animal models
  • numbers/more homogeneous genetic background






  • genes are on chromosomes and thus assumed to be
  • linked during transmission from one generation to
  • another
  • in reality linkage only holds for relative small
  • distances due to meiotic crossing over
  • linkage analysis: follow the pattern of inheritance of
  • polymorphic markers in pedigrees in which a disease
  • phenotype segregates
  • 1% recombination = 1cM
  • RFLP, minisatellites (VNTRs),
  • microsatellites or (CA)n repeats

odds of linkage = likelyhood for linkage/no linkage

LOD: logarithm of the odds ratio for linkage

LOD score >3 = significant linkage

<-2 = no significant linkage

haplotypes = sets of alleles on a small chromosome








association studies and LD
  • linkage disequilibrium: combination of closely linked
  • alleles, referred to as haplotypes, originating from a
  • single ancestral chromosome
  • apparently contradictory with the expected random
  • association assuming the occurrence of random CO
  • over many generations
  • cause: ‘founder’ mutations, recent mutations
  • studied by polymorphic markers (RFLPs, CA repeats
  • , more recently SNPs)
  • study of ‘inbred strains’ of mice or rats
Association studies for detection of disease genes

using linkage disequilibrium

  • Can we use SNPs for association studies in man
  • SNPs common and rare
  • SNPs coding and non coding
  • analysis of haplotypes and LD using SNPs
  • computer simulation and experimental data
  • suggest that LD extends only a few kb away
  • from SNPs
  • other data suggest > 100 kb
  • reasons for discrepany
  • small studies
  • different populations
Association studies for detection of disease genes

using linkage disequilibrium

Reich et al. Nature Genetics May 2001

rather large blocks of LD interspersed with

recombination hot spots

Association studies for detection of disease genes

using linkage disequilibrium

  • Study design (Reich et al. Nature Genetics May 2001)
  • 19 different chromosomal regions anchored
  • around a coding SNP
  • finished sequence for at least 160 kb (North European)
  • frequent minor (less common) allele
  • allows cross population comparison
  • possible with modest sample size
  • useful in search for common diseases
  • resequencing of 2 kb region at 0-5-10-20-40-80-160 kb
  • 272 high frequency polymorphisms
  • calculation of allele frequency and LD
Association studies for detection of disease genes

using linkage disequilibrium

  • Results (Reich et al. Nature Genetics May 2001)
  • relatively large blocks of LD
  • why?
  • Study of Yorubans, Nigerian population
  • common ancestry with NE around 100.000 yrs ago
  • similar allelic combinations at short distance
  • half length LD is less than 5 kb
  • Consequences
  • genome wide LD mapping probably possible but
  • limited resolution, choose other populations for
  • refined mapping
Mouse models
  • history: ~1900 ‘inbred strains of mice’
  • until ~1970s: difficulties in finding the responsible defects
  • later: linkage analysis, positional cloning,
  • genetic maps of mouse and man al lead to
  • identification of ‘single gene mutants’
  • development of powerful statistical programs lead
  • to ‘quantitative trait locus’ (QTL) analysis
  • advantages through inbreeding and controlled
  • environmental factors (eg nutrition)
  • knock out and transgenic mice
Genetics of ‘common diseases’
  • situation 1 (CHD)
  • rare monogenic disorders
  • known (metabolic, biochemical) pathways
  • situation 2 (obsesitas)
  • mouse models with monogenic traits
  • previously unknown metabolic pathways
Genetics of ‘common diseases’

coronary heart disease

  • frequent - high incidence, important impact on public health
  • ‘environmental’ and behavioural changes
  • increasing age
  • single gene disorders (rare) vs polygenic disorders (common)
  • multifactorial inheritance
  • multiple and complex genetic factors interacting with environment
  • Duchenne muscle dystrophy vs infectious disease
Genetics of ‘common diseases’

cardiovascular disease - atherosclerosis

  • hart attacks (infarct), stroke (thrombosis) and peripheral
  • vascular disease
  • occlusions in large and middle sized arteries
  • late onset as a result of chronic damage of vascular
  • endothelial cells
  • involved elements: LDL, thrombocytes, macrophages, lymphocytes,
  • smooth muscle cells of intima, invasion of fat particles in blood
  • vessels and formation of fibrocellular atheromatuos plaques
Geneticsof ‘common diseases’

CHD - atherosclerosis

  • CHD: coronary heart disease
  • multifactorial, no Mendelian segregation
  • genes involved in lipoprotein level, blood pressure,
  • diabetes, obesitas, blood coagulation, immune system,
  • blood vessel reactivity
  • environmental factors: smoking, nutrition, exercise
  • interindividual variation in disease susceptibility
  • predictors of risk:

- blood lipids (cholesterol)

- blood pressure

- blood coagulation factors

Geneticsof ‘common diseases’

cardiovascular disease

lipoprotein metabolisme

Exogenous pathway

Esterifaction of

fatty acids and cholesterol

Uptake of remnant particles in liver

by LDL receptor/LRP and chylomicron receptor

Triglycerids - cholesterol

Fat soluble vitamins



Remnant particle enriched with

cholesterol esters + apoB48 + apoE/C

Release of fatty acids (FFA) in

peripheral capillaries

Mediated by Lipoprotein lipase (LPL)

and co-factor apoCII

VLDL particle: central triglycerids and cholesterol packaged

with phospholipiden and one apoB100 molecule

Exogenous pathway

Esterifaction of

fatty acids and cholesterol

Uptake of remnant particles in liver

by LDL receptor/LRP and chylomicron receptor

Triglycerids - cholesterol

Fat soluble vitamins



Remnant particle enriched with

cholesterol esters + apoB48 + apoE/C

Release of fatty acids (FFA) in

peripheral capillaries

Mediated by Lipoprotein lipase (LPL)

and co-factor apoCII

Endogenous pathway

Synthesis of triglycerides and cholesterol

in the liver

Partial conversion of IDL to LDL by hydrolysis of

triglycerides to cholesteryl-ester,

removal of apo’s except apoB100

Partial clearance of IDL in liver by LDLR and apoE

Assembly of triglycerides

and cholesterol with phospho-

lipids/one apoB100 molecule

and many apoC/E molecules

into VLDL particles


Formation of VLDL remants (IDL)

after removal of triglycerids

Endogenous pathway

excess LDL molecules oxidise

Attract macrophages, transform into foam cells

upon LDL uptake, oxidation

Membrane and steroid hormone synthesis

Exogenous pathway: dietary lipid absorption and transport
  • absorption of fatty acids and cholesterol in intestinal aborptive cell
  • esterification to triglycerids and cholesterol-esters, respectively
  • transport to lymphatic system and into plasma in the form of
  • chylomicrons (triglyceride rich lipoproteins)
Exogenous pathway: dietary lipid absorption and transport
  • chylomicrons are large particles consisting of
  • core of triglycerids and cholesterol-esters
  • apolipoprotein apoB48 and small amounts of
  • apo CI, CII, CIII en E and A-IV
  • metabolised (hydrolyse) in peripheral capillaries to fatty acids as
  • energy source for skeletal muscle tissue or for storage in fat cells,
  • through the action of lipoproteine lipase (LPL) and apoCII as co-factor
  • following release of triglycerids, apoA en apoC are transferred to HDL by LPL,
  • chylomicron remnants (cholesterol-rich) are removed from circulation by
  • LDL receptor en LRP (low density lipoprotein receptor related
  • protein) mediated pathways in the liver
Endogenous pathway: hepatic lipoproteins
  • liver synthesises triglycerids and cholesterol, which together with residual
  • dietary fat, fat-soluble vitamins and apoB100
  • (1 molecule per VLDL partikel) are incorporated into VLDL particles and
  • secreted into circulation
  • aim: transport of fatty acids from liver to other tissues
  • functional form results through inclusion of apoE and apoCII en CIII from HDL
  • hydrolyse and removal of core-triglyceride by LPL
  • result: VLDL remnants = IDL (intermediate density lipoproteins)
  • 1/2 absorbed by liver via apoB (= ligand for LDL receptor)
  • 1/2 hydrolysed by hepatic lipase to LDL (cholesterol-ester rich)
hepatic lipoproteins (2)


  • - carries 60-70% of plasma cholesterol, delivers cholesterol to peripheral
  • tissues and to the liver for further metabolism and excretion in bile
  • (receptor mediated process)
  • - 75% taken up by liver via apoB100 (ligand for LDL receptor)
    • - 24% to peripheral tissues for membrane and steroid hormone biosynthesis
    • metabolic consequences of cholestrol uptake by cells
    • (1) decreased de novo cholesterol synthesis,
    • (2) increased conversion of cholesterol into cholesterolester
    • (=storage form of cholesterol)
    • (3) decreased expression of LDL receptors
    • - remaining 1% remains in circulation and can be modified by oxidation,
    • these oxidised LDL particles can attract ‘scavenger’ macrophages which
    • become foam cells as they ingest these particles
  • familial LPL and apoCII (=LPL co-factor) deficiency
    • - no hydrolysis of chilomicrons and VLDL resulting in
    • hypertriglyceridemia, no increased risk for atherosclerose
    • - 1/mio except in high risk populations (eg Quebec)
    • - low fat intake
  • FH, familial hypercholesterolaemia
  • - defect in LDL receptor gene: no LDL ‘clearance’ from circulation
  • (no r, precursor doens’t reach the membrane, r doens’t bind
  • LDL, hundreds of different mutations)
  • - HoZ (LDLx4-6) not older than 30 yr, HeZ (1/500)
  • 1/2 heart attack before age of 60 yr (LDLx2)
  • familial apoB100 defect
  • - one single mutation
  • - no binding of LDL to receptor
  • - HeZ increased LDL 50-100%
  • - 1/1000

search for ‘common variants’ in genes

influencing LDL content

  • linkage studies for three genes involved in LDL metabolism
  • in 150 families

CYP7: cholesterol 7-hydroxylase, enzyme involved in

bile acid production

  • other loci: 1p34, 13q, 15q25
  • Hyplip1
  • - mutant mouse strain for
  • familial combined hyperlipidemia (FCH) phenotype
  • - triglycerides and/or cholesterol raised plasma levels
  • - fine mapping of mouse locus
  • - 13 candidate genes: mRNA expression and sequencing
  • - thioredoxin interactin protein
OBESITAS: introduction (1)
  • body mass index (BMI) >30
  • increased risk for NIDDM, hypertension, CHD,
  • reproductive problems, etc...
  • 1/3 Amerikan population, increasing problem
  • in children
  • interaction between genetic, environmental and
  • psychosocial factors
  • energy homeostasis
OBESITAS: introduction(2)
  • obesitas genes identified
  • genetic predisposition
  • availability of food, composition,
  • excersise
  • “thrifty gene” hypothesis (Neel, 1999)
OBESITAS: introduciton(3)
  • energy balance
  • energy storage when energy intake is higher than total
  • expenditure
  • E-expenditure through physical activity,
  • basal metabolism and adaptive thermogenesis

control of energy-intake and body weight

  • behaviour, autonomous nervous system and
  • neuroendocrine
  • short term: start and stop eating due to hunger and
  • saturation, controled by neural and endocrine factors
  • long term eg by leptine = hormone produced
  • by fat cells
  • CNS ligand-receptor signal-
  • transduction pathways

‘single gene disorders’ mouse models for obesitas:

causative genes are identified

(agouti, fat, tubby, obese, diabetes)











leptine gereguleerde centrale melanocortine circuit

neuropeptide Y/Argp (Agouti related peptide)

- endogenous regulator of energy balance

- “feeding-inducing” neuropeptides

- strong expression at nucleus arcuatus


- leads to suppression of MC4R

(melanocortin 4 receptor)

- causes increased food intake

- decreases energy expenditure

- link with insuline is unclear, not the dominant

peripheral signal molecule

- first discovered orexigenic factor

neuropeptide Y/NPY receptors

- KO mouse: normal

NPY/leptin dubble KO: reduced effect of leptin KO

- KO for 6 known receptors

obesity instead of expected anorexigenic effect

reveals complexity of control mechanisms

and multifactorial control


- gain-of-function Argp mutant mouse:

obesity phenotype comparable with loss-of-function

for Pomc of Mc4r

- Ay mutation: ectopic expression of agouti

color, dominant obesity syndrome,

increased growth and yellow hair color

- related to Argp

leptin-leptin receptor

- leptos = thin

- hormone primarily produced by adipocyt

- belongs to cytokine family of proteins

- is responsible for complex neural respons incl

hunger, behavioural changes (search for food),

decreased metabolism, infertility...

leptin-leptin receptor

- communication concerning lon term energy storage

- other effects outside CNS: decreased

triglyceride accumulation in tissues other than fat

tissue (eg muscle, liver), contributes to

insuline resistance

- abscence of leptin signal in the presence of food

causes obesitas

- causes decreased expression of NPY/Argp

- induces starvation respons


- treatment by subcutaneous leptin injection

- 2 families with leptin mutatie

- AR

- HoZ for loss-of-function mutation


-1 family

- HoZ mutation responsable for truncation of the

cytoplasmatic domain

- class I cytokine receptor


- CART: cocaine and amphetamine related transcript

-MSH: derived from proopiomelanocortin (POMC)

- CART and POMC are induced by leptin (anorexigenic)

- produced by two neuronal populations within the


- POMC: twchildren with HoZ or compound HoZ

for loss-of-function mutation


- hypothalamic homologue of MC1R (receptor

in melanocytes)

- KO: melanocortin obesity syndrome = agouti

but without yellow hair color

- mutation in humans are responsible for

4-5%of obesity cases (haploinsufficiency,

not dominant negative)

Other genes
  • neuropeptide processing enzyme
  • - carboxypeptidase E: exclusively in mouse (fat)
  • - PC-1: discovered in man
  • complex obesity syndromes in mouse and man
  • probably as a results of POMC processing
  • MC3R: obesity in mouse
  • UCP and BAT (brown adipose tissue)
QTL analysis in mice: search for obesity genes
  • effect of individual genes on energy expenditure,
  • hyperphagia and fat storage
  • study of the effect of dietary composition
  • more than 70 loci identified in mice

blue: whole genome scan human

red: mouse QTLs

green: human monogenic mutations

Breakthrough in genetic studies on common diseases
  • ADAM33 gene in asthma (Nature 418:426, 2002)
  • G72 in schizophrenia (PNAS 99:13675, 2002)