L53: Multifactorial Diseases

Question 1

Explain why the recurrence risk for multifactorial diseases changes every time a relative is diagnosed with the disorder

Answer 1

• In multifactorial disease, it is usually not known how many contributing alleles there are in the parent generation - The birth of each affected child provides information which allows calculating the risk more accurately - The more affected children are born to a couple, the higher the assumed number of contributing alleles in the parent generation. Every time an affected child is born into a family, the recurrence risk has to be corrected upwards

Question 1

Give general prevalence figures for common multifactorial birth defects

Answer 1

• Risk for general population = 0.5% risk - If second degree relative affected = 0.7-2% risk - If first degree relative affected = 3-4% risk - If two first degree relatives affected = 5-8% risk - Three first degree relatives affected = 9-12% risk - Identical twin = 20-30% risk

Question 3

Explain how one can estimate the number of genes involved in the inheritance of a quantitative trait

Answer 3

• Quantitative traits include things such as height, weight and blood pressure. - More than one gene contributes to these phenotypes - Each allele can be contributing or noncontributing to the trait. In a trait involving two genes, there can be 5 classes of phenotypes (aabb, AABB, aABb and rest of combinations) - The more genes involved, the more classes of phenotypes can be observed and the more the distribution of phenotypes resembles a bell curve. - To estimate: the more genes involved, the lower the probability of an offspring inheriting all or none of the contributing alles, this means that the higher the number of genes involved, the lower the fraction of extreme phenotypes are at the fringes of the bell curve.

Question 4

Describe the role of HLA haplotypes in the development of type 1 diabetes and other autoimmune disorders

Answer 4

• Think of haplotypes as blocks of genetic information that are inherited together. HLA haplotypes are expressed in a codominant manner. Each parent only transmits one haplotype to the child. Certain HLA haplotypes favor or protect against diseases. - T1D: Contribution of HLA haplotypes to risk for T1D is strong, but not exclusive – only accounting for ~40% of genetic risk. Genetic variation in DR-DQ haplotypes affects risk for T1D. Some DR-DQ haplotypes increases risk and are known as susceptibility alleles. Others decrease risk and are designated protective alleles - Other immune disorders: HLA-B haplotypes determine risk for spondyloarthropathy. HLA-C haplotypes predict risk for psoriatic arthritis.

Question 5

Describe how the family history or the pts genotype influence the prediction of risk (relative risk ratio and relative risk)

Answer 5

• Incidence and prevalence data are different for ppl with different numbers of affected relatives. - In diseases with strong genetic component, prevalence for ppl with affected relatives is much higher than for general population - Therefore a measure known as relative risk ratio (lamda r where r indicates relationship) compares frequency of a dz in relatives of affected and unaffected probands. - Lambda r = prevalence of dz in relative r of affected person divided by prevalence in general population - Relative risk is a way to describe disease association of an allele: how much more likely a carrier of an allele is to develop the dz than a non-carrier. If RR for carrying allele Y is 3.5 then we tell pts: your risk is 3.5 times the risk of a non-carrier of allele Y

Question 6

Explain the statistical measures that describe the risk for multifactorial diseases in general populations

Answer 6

• Incidence: how many new cases are recorded in a given time divided by size of population - Prevalence: proportion of population that is affected by the dz at any given time

Question 7

Explain how the genetic and the environmental influences on complex disease can be estimated

Answer 7

• Twin and adoption studies (MZ vs DZ twins) - Concordant trait = trait shared by both twins - Discordant trait = trait not shared by both twins - Diseases with significant genetic component will show higher concordance rate in MZ twins than in DZ twins using crude measure known as heritability H2 - H2 = (concordance MZ – concordance DZ) x 2 - High heritability = trait is determined predominantly by genetic factors

Question 8

Explain the mapping of multiple contributing alleles

Answer 8

• Use of linkage analysis. - Genome of affected sib pairs is analyzed for presence of shared SNP markers - Loci that are shared by affected siblings significantly more than as can be expected by chance alone are likely to be involved in the etiology of the disease - Also, model-free linkage analysis: analyze whole genome for SNP markers in affected families by looking for markers linked to disease

Question 9

Explain the gender-specific differences in recurrence risk for multifactorial disorders such as pyloric stenosis

Answer 9

• Pyloric stenosis is more common in male birth 1/200 than in female birth 1/1000. Accordingly, in pyloric stenosis, there is a lower threshold for males (males need few contributing alleles) and a higher threshold for females (females need more contributing alleles). - When assessing recurrence risk then: affected female proband has more contributing alleles than affected male proband and therefore has higher risk of having an affected sibling than does a male proband. Also her risk of having an affected brother is higher than her having an affected sister because a brother would only need fewer contributing alleles to develop a disease. - Affected male proband has higher recurrence risk for having a brother than a sister with pyloric stenosis.

Question 10

Contrast the pedigrees for multifactorial inheritance and autosomal dominant inheritance

Answer 10

• Multifactorial inheritance pedigrees most closely resemble pedigrees for autosomal dominant inheritance with incomplete penetrance - 4 characteristics of MF diseases set them apart from single-gene disorders 1.) Don’t follow Mendelian patterns of inheritance 2.) Shows familiar aggregation – number of contributing alleles is high in affected families 3.) Frequently show incomplete penetrance d/t environmental factors on the development of the disease. 4.) Disease is much more common among close relatives of proband than it is among less closely related persons