13 12 07 Polygenic Multifactorial

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Polygenic and multifactorial

diseases

-key features and isolation of

responsible genesNewcastle; 13th December 2007


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Early genetics

Two camps

Followers of Mendel

Dichotomous traits

Believed that traits presented in predictable patterns of

inheritance (AD, AR, XLD, XLR & Y linked)

Biometricians

Continuous/qualitative traits eg height, weight

Not amenable to Mendels laws as variable from individual

to individual

Two camps married by demonstration that these continuous traits

could be governed by a large number of independent genes each

governed by Mendels law


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Polygenic/Multifactorial inheritance

These findings form the basis of polygenic and multifactorial

inheritance and are now known to account for qualitative traits

such as height, weight, blood pressure ..

..and also for the common diseases that do not follow

Mendelian inheritance patterns and represent major healthproblems such as heart disease, obesity, asthma, diabetes and

cancer

Estimated that lifetime risk of genetically influenced

common disorder in Western population is 60%


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Mendelian and complex diseases

No of

disease

proteins

Affecteds

per 1000

popn

In utero

to pubertyPuberty of age 50 Over 50

Lung

Diabetes

Heart/circulatory

Athritis/musculoskeletal

18-44 45-54 55-64

Age range

Bjornnson et al 2004; TIGS Vol 20(8):350-358

Mendelian

complex


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Polygenic/Multifactorial diseases

Following success in identification of the majority of single gene

disorders eg CF, HD, DMD etc

New interest in identifying genes responsible for these common

complex diseases Improved technologies

Pharmaceutical company interest

Hope for designer medicine


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Key concept of complex diseases

Multiple distinct loci interact with/without other factors including the environment

to result in end stage phenotype

Expressed in population as a continuously variable susceptibility that follows

Gaussian distribution

Effectively creates a gradient of susceptibility - phenotype presents beyond a

certain threshold

Threshold of liability

population mean

Affected individuals


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Key concepts of complex disease

Familial concentration of disease without specific pattern of inheritance

Absence of clear biochemical defect resulting from single abnormal

gene

Considerable variation in severity and expression of phenotype

(between and within families)

Most affected individuals have unaffected parents

Often sex differences


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Familial clustering

Threshold of liabilitypopn mean

Affected individuals

Threshold of liability

popn mean

Affected sibs

sib mean

General population

Siblings of affected

individuals


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Recurrence risks

Affected individuals have inherited combination of high susceptibilityalleles.

Relatives share these alleles

Thus cousins, aunts, uncles etc also at higher risk than general

population

Parents with affected child have higher than average number of highrisk alleles Recurrence risk is higher if >1 family member affected

Greater the severity of the disease the higher the recurrence risk


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Sex differences

Recurrence risk is greater if proband is of less commonly affected

sex

Eg Congenital pyloric stenosis

Male probands Recurrence in brothers 3.8%

Recurrence in sisters 2.7%

Female proband

Recurrence in brothers 9.2%

Recurrence in sisters 3.8%


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Cleft lip and palate


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Genetic basis of complex disease

Classic scale of human disease

Single gene disorder polygenic multifactorial

(single major locus (several loci (many loci and

environment>phenotype) >phenotype) >phenotype

Now seen as an oversimplification


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Single gene disorders

single gene disorders are now known to represent disorders in whicha single major locus is necessary and sufficient to result in thephenotype

Usually extensive allelic and non allelic heterogeneity

but where the phenotype can differ in intra and inter familial mannerdue to modifier genes and environment

eg in CF many mutations identified in the CFTR gene

good degree of correlation with CF mutation and pancreatic disease

severity of pulmonary disease shows no such correlation

now known that expression of CFTR gene is modified by a number of otherfactors including variants at NOS1, HLAIII, TNFA, TGBF1, CFM etc


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Polygenic diseases

digenic inheritance where defects at two loci are necessary to result inphenotype

eg retinitis pigmentosa; peripherin-RDS, ROM1

trigenic inheritance, where defects in 3 loci/ alleles are necessary roresult in phenotype

eg Bardet Biedl; BBS2/BBS6

oligogenic inheritance where several loci are involved in resultingphenotype


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Multifactorial diseases

Increasing no of loci involved

~18 different loci identified as being involved in diabetes

Approximately 40% familial clustering due to the HLA loci

(lS=3); other involved include INS (1.9), CTL4 (1.2)

Each locus involved is neither sufficient or necessary to result inthe phenotype

Also environmental factors


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Models to explain multifactorial disease

2 basic models

Common disease - common variant(restricted polymorphism model)Proposed that there is a small number of loci with risk alleles that are common inthe population (>1%) and each exerts a considerable genetic effecteg. APOEe4allele in Alzheimer disease; Factor V Leiden in deep venous thrombosis

Common disease - rare variantSuggested that there are a large number of loci with risk alleles that are rare inthe population (


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Other factors

Environmental influence - diet, exposure to toxins, exercise etc

Epistasis - interaction between different loci;where one particular allele

at locus 1 prevents particular allele at locus 2 from manifesting its effect

Somatic changes

Epigenetics - methylation, imprinting etc

All combine to produce disease state in individual


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An example of epistasis


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Identification of responsible genes

Linkage analysis and association analysis are the 2 main strategies

Linkagerefers to the physical coupling between 2 loci (marker locus

and disease locus

indicates close proximity of marker to disease locus

Association studiesrefers to the co occurrence of two variants

(particular allele of marker and phenotype)

indicates particular allele of marker (or one very close to it) is causative

in disease


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Linkage studies

Classic linkage studies require Large mulitgenerational single family (or multiple smaller families in clear

homogeneous disease)

Defined mode of inheritance

Single locus responsible

Known penetrance

Genetic homogeneity Clearly not the case in complex diseases

however can still be used in non parametric models under different modes ofinheritance, allowing for heterogeneity etc

thus likelihood of detecting causative locus less than in single major locusdisorders

alleles of low or moderate genetic effect unlikely to be identified


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Association studies

Several methods available including Case control series

Affected sib pair

Affected pedigree member

TDT

Each has different advantages, disadvantages and limitations

Complex statistical analysis

Can be influenced by

Sample size, selection of controls

Population stratification, admixture

Epistasis, age of disease

Problems in multiple testing

Informativeness, density of markers

Level of risk alleles effect in disease


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Association studies- population based

Case-control study Most widely applied strategy

Series of affected patients vs series of matched controls

Cases readily obtained; genotyping easy

Most prone to producing false positive results - usually due to incorrectcontrol population selection. Any difference in allele frequencybetween groups may be due to differences between populations(independent of disease)

Require significant numbers to adequately power study (1000s vs100s); especially important in study of multiple variables

Case -cohort study Cases and controls drawn from selected population under study to

investigate broad spectrum of diseases and factors

Prospective; takes longer to select sufficient numbers


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Association studies - family based methods

Affected sib pair method

Tests for increased inheritance of particular allele in sibs vscontrols

Identity by descent more powerful than identity by state

IBD requires parental testing (IBS does not)

Affected pedigree member method Additional family members tested; similar to ASP

Discordant trios

Useful if parental samples unavailable


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TDT

Transmission disequilibrium testing

Requires testing of parental and affected offspring and classifies

alleles transmitted to affected children and not transmitted

Test for Requires that parents are heterozygous

Power lost if parents are homozygous Provides a joint test of linkage and association

Eliminates stratification effects

Can be modified to account for multi-allelic markers, multiple

siblings, missing parental data and quantitative straits


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Factors influencing success of studies

Control populations (stratification)

family based controls vs matched controls

Study population

inbred populations reduce number of segregating loci and non

allelic heterogeneity

admixture; eg Latin American, African American; creates

disequilibrium that breaks down rapidly for unlinked markers;

utilised in MALD (mapping by admixture linkage disequilibrium)

Epistasis; interaction between alleles can be accounted for by

statisitical models (Markov chain Monte Carlo based methodology)


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Factors influencing success of studies

Age of disease

old ancient diseases (restricted polymorphism model) have low rangeof linkage disequilibrium (~3kb). Requires high density map of markersto detect association

new diseases have high range of disequilibrium ( 10kb). Low densityscans required but low power to detect

Genetic effects of risk allele Few loci exerting considerable effect

Power to detect reduces with increasing no of loci

Informativeness of markers

power to detect decreases with reduced heterozygosity

Inference of linear distance Distance between marker and disease not easy to predict due to non

linear relationship between LD and distance below 60kb


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Identification of risk alleles

Linkage/association studies to locate regions of interest

Finer mapping of regions

Sequence analysis of candidate genes within interval

Numerous sequence variants likely to be present

Role of identified variants? Combination of variants?? Logisticalchallenge

Functional tests of candidates; cellular testing, knock out/in

models etc


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Polygenic/Multifactorial diseases

Encompass latter end of spectrum of human disease

Result from combination of numerous loci each of which is

neither sufficient nor necessary to result in disease

Identified by combination of linkage and association studies

Statistical and logistical issues


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Selected references

Bjornsson et al (2004) TIGS Vol 20(8):350-358

Weeks and Lathrop (1995) TIGS Vol 11(12); 513-519

Smith & OBrien (2005) Nature Review Genetics online pub 12 July; 1-10

Cardon & Bell (2001) Nature Review Genetics Vol 2; 91-99

Laird & Lange (2006) Nature Review Genetics Vol 7; 385-394

Wright et al (1999) Nature Genetics Vol 23; 397-404

Badano & Katsanis (2002) Nature Review Genetics Vol 3; 779-789 Wright et al (2003) TIGS Vol 19 (2); 97-106

Antonarakis & Beckman (2006) Vol 7; 277-282

Lanpher et al (2006) Nature Review Genetics Vol 7; 449-460

Concannon et al (2005) Diabetes Vol 54; 2995-3001

& Strachan & Read

13 12 07 Polygenic Multifactorial

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