1. Diseases with Complex Patterns of Inheritance (multifactorial disorders)

2. Table 8-1. Frequency of Different Types of Genetic Disease
Incidence at Birth (per 1000)
Prevalence at Age 25 Years
(per 1000)
Population Prevalence*
Disorders due to genome and chromosome mutations 6
1.8
3.8
Disorders due to single-gene mutations 10
3.6 20
Disorders with multifactorial inheritance
~50
~600
* All ages
Data from Rimoin DL, Connor JM, Pyeritz RE: Emery and Rimoin's Principles and Practice of Medical Genetics, 3rd ed. Edinburgh, Churchill Livingstone, If one estimate frequencies of congenital disorders based on number of pregnancies, chromosomal abnormalities would rank first with about 80 per 1000, but most of such pregnancies terminate in a miscarriage and not a live birth.

3. Comparison of Mendelian and complex traits and their inheritance
Mendelian traits are qualitative or dichotomous - either present or absent
Mendelian traits are almost always attributable to different alleles of single genes
Mendelian traits follow simple rules of inheritance, permitting recurrence risk to be calculated for family members
Complex traits can be either continuous (quantitative) like height, weight and IQ, or qualitative (present or absent) like type 2 diabetes; cardiovascular disease
Complex traits result from the contributions of multiple genes with or without environmental influences
Recurrence risk for a family member is determined using empirically derived risk tables
Large scale studies to identify genetic risk factors for diseases may make it possible to estimate an individual’s risk by sequencing his or her genome

4. Quantitative Traits are Described by a Normal or Gaussian Distribution about a population mean
X is the numerical value for the quantitative trait (e.g height).
Y is the number of individuals in the population that have the given value of X.
σ is the standard deviation of the mean, which is equal to the √variance. Y X
Shape of graph governed by two quantities:
Mean (m): average of values
Variance (s 2): measure of degree of spread to either side of mean; SD=s

5. Multigenic Theory of Quantitative Traits: example height
Traits governed by a large # of factors (genes) would display same type of continuous distribution as seen for quantitative traits

6. Polygenic theory of discontinuous traits
If continuous distribution of values about a population mean, how can polygenic disorders be dichotomous (yes/no)? Threshold

7. Family aggregation of qualitative traits
Family members share a greater number of the identical alleles of genes than unrelated individuals.
The recurrence risk for a genetic disorder within a family exceeds the frequency of the disease in the general population.
The relative risk ratio λr is a quantitative measure of the degree of familial aggregation of a disease.
Values of λr >> 1 suggests genes contribute to the disease

8. Family aggregation of qualitative traits
Family members share a greater number of the identical alleles of genes than unrelated individuals.
The recurrence risk for a genetic disorder within a family exceeds the frequency of the disease in the general population.
The relative risk ratio λr is a quantitative measure of the degree of familial aggregation of a disease.
Values of λr >> 1 suggests genes contribute to the disease
However, family members may also share environmental factors in common

9. Table Risk Ratios λr for Siblings of Probands with Diseases with Familial Aggregation and Complex Inheritance
Disease
Relationship λr
Schizophrenia
Siblings 12
Autism
150
Manic-depressive (bipolar) disorder 7
Type 1 diabetes mellitus 35
Crohn's disease 25
Multiple sclerosis 24
Data from Rimoin DL, Connor JM, Pyeritz RE: Emery and Rimoin's Principles and Practice of Medical Genetics, 3rd ed. Edinburgh, Churchill Livingstone, 1997; and King RA, Rotter JI, Motulsky AG: The Genetic Basis of Common Diseases, 2nd ed. Oxford, England, Oxford University Press, 2002.

10. Case control studies: a comparison of the frequency of a disease in an extended family to that of a control family
(matched for age and ethnicity)
Subjects
Relationship to subject
Frequency of MS in siblings (%)
Patients with MS
siblings
3.5
Patients’ spouses
0.2
MS: Multiple Sclerosis
Subjects
Frequency of PD disease in the subject group (%)
1st and 2nd degree relatives of Parkinson patients
6.3
Control group matched for age, sex, and ethnicity
1.2
PD: Parkinson Disease

11. Concordance and allele sharing among relatives
Concordance: likelihood that an individual will share a common phenotype with another family member (e.g. be affected by the same disease)
The number of alleles two family members share in common is determined by their degree of relatedness:
close relatives more likely to share alleles and to be concordant for a disease that has a genetic component than distant relatives
Table 8-3. Degree of Relationship and the Average Proportion of Alleles in Common
Relationship to Proband
Proportion of Alleles in Common with the Proband (%)
Monozygotic twin
1 (100%)
First-degree relative
1/2 (50%)
Second-degree relative
1/4 (25%)
Third-degree relative
1/8 (12.5%)

12. Table 8-4. Concordance Rates in MZ and DZ Twins
Concordance (%)
Disorder MZ DZ
Nontraumatic epilepsy 70 6
Multiple sclerosis
17.8 2
Type 1 diabetes 40
4.8
Schizophrenia 46 15
Bipolar disease 62 8
Osteoarthritis 32 16
Rheumatoid arthritis
12.3
3.5
Psoriasis 72
Cleft lip with or without cleft palate 30
Systemic lupus erythematosus 22
Concordance rate in monozygotic twins of less than 100% indicates factors other than genes contribute to a disease
Greater concordance rate in monozygotic twins compared to dizygotic twins is evidence of a genetic component because environmental factors are likely to be similar within a family
Not shown, similar concordance rates for monzygotic twins reared apart and those reared together suggests that genetic factors are more important than environmental factors

13. Assessing the contribution of genes and environment to quantitative traits and the concept of heritability

14. Height is a quantitative trait that follows a Gaussian distribution
Height is a quantitative trait that follows a Gaussian distribution. Distribution of values for quantitative traits in a population usually take the form of a normal or Gaussian distribution
Distribution of height in a sample of 91,163 young English males in 1939.

15. The variance of a normal distribution determines its breadth.
The variance (breadth of the distribution) is related to the contribution of genes and environment.

16. The variance of a normal distribution determines its breadth.
The variance (breadth of the distribution) is related to the contribution of genes and environment.
Variances are additive when they are due to different causes

17. The variance of a normal distribution determines its breadth.
The variance (breadth of the distribution) is related to the contribution of genes and environment.
Variances are additive when they are due to different causes.
The variance of a quantitative property is the sum of the variances due to genes and environment, vp = ve + vg

18. Variances of a normal distribution are additive when due to individual causes
vp = ve + vg
and
p2 = e2 + g2

19. The heritability of a trait (h2) is the proportion of the total variance that is due to genes
h2 = vg/(ve + vg)
vMZ = ve
vDZ = ve + vg
Variance in DZ pairs – Variance in MZ pairs
Variance in DZ pairs
h2 =
h2 =0: variability almost all due to environment
h2 =1: variability in due almost entirely to genes

20. Examples of complex disorders for which genetic and/or environmental factors are known.
Multiple genes
Genes and environment

21. Digenic Retinitis Pigmentosa
Incurable eye condition: progresses from night blindness tunnel vision  legal blindness by middle age
Simplest example of multigenic trait—determined by additive effect of genotypes at multiple loci
No known environmental factors
2 photoreceptor proteins associate noncovalently in photoreceptors in retina:
Peripherin
ROM1
Mutants of both must be present to cross threshold of cell damage, photoreceptor death and loss of vision

22. Digenic Retinitis Pigmentosa

23. Hirschsprung Disease (HSCR)
(more complicated)
Developmental abnormality of parasympathetic nervous system in gut
Affects ganglion cells of colon no peristalsis
severe constipation
symptoms of intestinal obstruction
massive colon dilation (megacolon) proximal to aganglionic segment
1/5000 newborns
Complex genetics:
-relative risk in siblings high: ls about 200
-but MZ twins not show perfect concordance
-can occur through multiple generations, affect multiple siblings or both,
Loss of a number of different genes can cause disease (locus heterogeneity): different forms behave as dominant, recessive or multigenic disorder (but risks not 50% or 25%)
-males: 2-fold higher risk compared with females in same family

24. Hirschsprung Disease (HSCR)
Multifactorial disease: results from additive effects of susceptibility loci at these, plus a number of other loci
-RET gene at 10q11.2 loss vs. partial function vs. unknown
-gene variants may be subtle in how they exert their effects, and affect on penetrance and expressivity

25. Empirical Risks for Counseling in Type 1 Diabetes
Develops in childhood; thought to be autoimmune disease with strong genetic component
Genes of the major histocompatibility complex on the p arm of chromosome 6

26. Idiopathic Cerebral Vein Thrombosis
Multigenic plus environmental influence
Clots form in venous system of brain, cause catastrophic occlusion of cerebral veins in absence of inciting event (ie infection or tumor)
Affects young adults
Rare, but with high mortality rate: 5-30%
Three relatively common factors
-2 genetic + 1 environmental
-each individually increase risk

27. Idiopathic Cerebral Vein Thrombosis* †
* Mutant allele of factor V (Arg506Gly, factor V Leiden) decreases factor Va degradation by protein C. The carrier (heterozygote) frequency is ~5% among Caucasians, and increases their risk of cerebral vein thrombosis by about 7-9 fold.
†Mutant allele of prothrombin, 20210G>A in the 3’ untranslated region of the mRNA increased prothrombin mRNA stability and plasma levels of the prothrombin protein. The carrier frequency is ~2.5% among Caucasians, and increases their risk of cerebral vein thrombosis by about 4-6 fold.
Oral contraceptives increase plasma levels of factor X and prothrombin, and when combined with either of the two mutations above, increases the risk of cerebral vein thrombosis by about 20 fold (Arterioscler Thromb Vasc Biol 22: , 2002).

28. Table 8-6. Cumulative Age- and Sex-Specific Risks for Alzheimer Disease and Dementia
Time Interval Past 65 Years of Age
Risk for Development of AD (%)
Risk for Development of any Dementia (%)
65 to 80 years
  Male
6.3
10.9
  Female 12 19
65 to 100 years 25
32.8
28.1 45
Data from Seshadri S, Wolf PA, Beiser A, et al: Lifetime risk of dementia and Alzheimer's disease. The impact of mortality on risk estimates in the Framingham Study. Neurology 49: , 1997.
AD: fatal neurodegenerative disease; affects 1-2% of US; most common cause of dementia in elderly; responsible for > half of all cases of dementia
All dementias: chronic, progressive loss of memory and other intellectual functions, associated with death of cortical neurons
AD: most significant risk factors: age, gender, family history
AD: definitive postmortem diagnosis: protein aggregates (b amyloid plaques neurofibrillary tangles)
AD: common form-late onset (>60yrs); no obvious Mendelian inheritance; yes familial aggregation and elevated relative risk ratio

29. Chance of developing Alzheimer disease as a function of age for different APOE alleles
Apolipoprotein E (APOE) locus: first significant genetic factor associated with common late onset AD—is constituent of AD amyloid plaques
e4: predisposing allele: predisposes but not predestine any individual

30. Frequency of genotypes with and without APOE e4 allele among AD patients & controls in US and Japan

31. Some Common Congenital Malformations occurring as isolated defects (not as parts of a syndrome) are Complex Disorders with Contributions from Genes and Environment

32. Table 8-8. Some Common Congenital Malformations with Multifactorial Inheritance
Population Incidence (per 1000)
Cleft lip with or without cleft palate
Cleft palate
0.4
Congenital dislocation of hip 2*
Congenital heart defects
4-8
   Ventricular septal defect
1.7
    Patent ductus arteriosus
0.5
    Atrial septal defect
1.0
   Aortic stenosis
Neural tube defects
2-10
   Spina bifida and anencephaly
Variable
Pyloric stenosis
1†, 5*
*Per 1000 males. †Per 1000 females. Note: Population incidence is approximate. Many of these disorders are heterogeneous and are usually but not invariably multifactorial. Data from Carter CO: Genetics of common single malformations. Br Med Bull 32:21-26, 1976; Nora JJ: Multifactorial inheritance hypothesis for the etiology of congenital heart diseases: the genetic environmental interaction. Circulation 38: , 1968; and Lin AE, Garver KL: Genetic counseling for congenital heart defects. J Pediatr 113: , 1988.

33. Anencephaly (incomplete development of the brain) and spina bifida are neural tube defects (NTDs)
Neural tube defects are complex disorders having multigenic and environmental causes. However, a single leading cause was discovered to be a deficiency of the vitamin folic acid. Folic acid supplementation has been found to reduce the disease by 75%.

34. Table Empirical Risks for Cleft Lip with or without Cleft Palate in Relatives of Affected Probands
Population Affected with CL(P)
Incidence (%)
λrelative
General Population
0.1 —
First-degree relatives
4.0 40
Second-degree relatives
0.7 7
Third-degree relatives
0.3 3
For fourth-degree relatives, the incidence and risk ratios approach those of the general population.

35. Mental illnesses affect about 4% of the human population worldwide
Schizophrenia and bipolar disorder likely to be multigenic but genes not known;
Counseling relies on empirical risk tables
Table Recurrence Risks and Relative Risk Ratios in Schizophrenia Families
Relation to Individual Affected by Schizophrenia
Recurrence Risk (%) λr
Child of two schizophrenic parents 46 23
Child
9-16
11.5
Sibling
8-14 11
Nephew or niece
1-4
2.5
Uncle or aunt 2
First cousin
2-6 4
Grandchild
2-8 5

36. Table 8-14. Recurrence Risks and Relative Risk Ratios in Bipolar Disorder Families
Relation to Individual Affected with Bipolar Disease
Recurrence Risk (%)* λr
Child of two parents with bipolar disease
50-70 75
Child 27 34
Sibling
20-30 31
Second-degree relative 5 6