1. Chapter 12 Multifactorial Inheritance and Common Disease

2. GENETIC ENVIRONMENTAL Duchenne muscular dystrophy Haemophilia Osteogenesis imperfecta Club foot Pyloric stenosis Dislocation of hip Peptic ulcer Diabetes Tuberculosis Phenylketonuria Galactosaemia Spina bifida Ischaemic heart disease Ankylosing spondylitis Scurvy Rare Genetics simple Unifactorial High recurrence rate Common Genetics complex Multifactorial Low recurrence rate The contributions of genetic and environmental factors to human diseases

3. Continuous (quantitative) characters Polygenic – many genes Large number of genetic factors, each making only a small contribution to the final phenotype

4. Multifactorial inheritance Inheritance controlled by many genes with small additive effects (polygenic) plus the effects of the environment Clinical clue: One organ system affected environment PotentialActual GenotypePhenotype (genes) (appearance)

5. Principles of Multifactorial Inheritance The Basic Model Polygenic traits Multifactorial traits (quantitative traits: blood pressure, height, etc) individual genes in multifactorial inheritance : Mendelian principles of segregation and independent assortment, but acting together No.of individuals in population Liability In multifactorial disorders, the liability curve is made up of genetic and environmental factors Low liability Average liability High liability

6. Principles of Multifactorial Inheritance The Threshold Model threshold of liability for a disease expression eg. pyloric stenosis 1/200 for male, 1/1000 for female (total 3/1000) two thresholds for male and female requirement of fewer disease-causing factors in males In multifactorial disorders, there is a threshold, above which a person will develop the multifactorial disorder

8. Multifactorial Inheritance  anencephaly  atopic allergies  cleft lip/palate  club foot  congenital heart disease  congential hip dysplasia  congenital scoliosis  diabetes mellitus  epilepsy  hydrocephalus  hyperlipidemias  manic depressive psychoses  non-specific MR  NTD  presenile dementias  pyloric stenosis  schizophrenia  urinary tract malformations

9. Multifactorial genetic diseases The recurrence risk is higher if more than one family member is affected. More severe expression of the disease → a higher recurrence risk Proband of less commonly affected sex → a higher recurrence risk Rapid decrease of recurrence risk in relatives Prevalence in a population (f) risks for offsprings and siblings of probands: √1

10. Multifactorial genetic diseases The recurrence risk is higher if more than one family member is affected. More severe expression of the disease → a higher recurrence risk Proband of less commonly affected sex → a higher recurrence risk Rapid decrease of recurrence risk in relatives Prevalence in a population (f) risks for offsprings and siblings of probands: √1

11. Family studies of the incidence of cleft lip (± cleft palate) The more severe the manifestation of a multifactorial condition, the greater the probability of recurrence

12. Multifactorial genetic diseases The recurrence risk is higher if more than one family member is affected. More severe expression of the disease → a higher recurrence risk Proband of less commonly affected sex → a higher recurrence risk Rapid decrease of recurrence risk in relatives Prevalence in a population (f) risks for offsprings and siblings of probands: √1

13. Some multifactorial conditions have an unequal sex ratio For some conditions there must be a different threshold for males and females

14. Frequency of pyloric stenosis in relatives For a female to be affected with pyloric stenosis, she must have a particularly strong genetic susceptibility

15. Multifactorial genetic diseases The recurrence risk is higher if more than one family member is affected. More severe expression of the disease → a higher recurrence risk Proband of less commonly affected sex → a higher recurrence risk Rapid decrease of recurrence risk in relatives Prevalence in a population (f) risks for offsprings and siblings of probands: √1

16. 0.05

17. Risk to Relatives for Same Malformation as Index Case MalformationRisk (population risk compared to degree of relationship) PopFirstSecondThird Cleft lip/palate1/100030x7x3x Congenital dislocation/hip1/100040x4x1.5x Pyloric stenosis1/100020x5x 2x Clubfoot1/100020x5x 2x Anencephaly/spina bifida1/5008x2x

18. Multifactorial genetic diseases The recurrence risk is higher if more than one family member is affected. More severe expression of the disease → a higher recurrence risk Proband of less commonly affected sex → a higher recurrence risk Rapid decrease of recurrence risk in relatives If prevalence in a population is f, a risk for offspring and siblings of probands is √1.

19. A genetic trait affected by a combination of a single gene and a multifactorial background

20. How evidence is gathered for genetic factors in complex diseases Familial risks (what is the incidence of a disorder in relatives compared with the incidence in the general population?) Twin studies (what is the incidence in monozygotic compared with dizygotic twins?) Adoption studies (what is the incidence in adopted children of the disorders which their parent had?) Population and Migration studies (what is the incidence in people from a particular ancestry group when they move to a different geographical area?) Evidence from these types of studies can estimate the heritability of a condition - the proportion of the aetiology ascribed to genetic factors rather than environmental factors

21. Proband Siblings of proband Families with one child with multifactorial condition 50 brothers and sisters Estimation of familial risks

22. Proband Siblings of proband 50 brothers and sisters 2 affected with multifactorial condition Families with one child with multifactorial condition Estimation of familial risks

23. ProbandSiblings of proband Therefore probability of recurrence = 1/25 (4%) 2/50 affected with multifactorial condition Families with one child with multifactorial condition Estimation of familial risks

24. Twin study - Nature or Nurture? Twin Studies concordant/discordant in monozygotic (identical) twins/dizygotic (fraternal) twins intraclass correlation coefficients (concordance and correlation rates, - 1.0~1.0) MZ, determined entirely by genes: 1.0 MZ, no similarity: 0.0 DZ, determined entirely by genes: 0.5 Heritability (h) h=2(C MZ -C DZ ), C MZ : concordance rate for MZ, C DZ : concordance rate for DZ determined largely by gene: C MZ → 1.0, C DZ → 0.5, therefore, h → 1.0 Difficulties in twin studies the similar environments of MZ and DZ twins somatic mutations during mitotic divisions uterine environments of different pairs of MZ different methylation patterns → study with MZ twins who were raised in separate environment

26. Adoption study - Nature or Nurture? Adopted children from affected parents develop a disease more often than those from normal parents. Cautions for adoption studies prenatal environment adoption after several years old intentional matching of adoptive parents with natural parents Providing a preliminary indication of the multifactorial disease extent caused by genetic factors

27. Congenital Malformations 2% of newborn: 1-5% recurrence risks of sibling associated with these disorders Isolated malformations/associated malformations Causes Genetic factors HOX, PAX, and TBX gene families RET proto-oncogene (Hirschsprung disease) Genetic factors contributing to many congenital malformations are yet unidentified. Environmental factors thalidomide → phocomelia retinoic acid → defects of heart, ears, and CNS rubella infection → heart defects

30. Coronary artery disease (CAD) by atherosclerosis risk factors: obesity, smoking, hypertension, cholesterol, family history related genes: LDL receptor genes, apolipoprotein genes, etc.

32. Cardiomyopathy hypertrophic cardiomyopathy 50% familial, AD β-myosin heavy chain, myosin-binding protein C, or troponin T dilated cardiomyopathy 30% familial actin, troponin T, desmin, and components of dystroglycan- sarcoglycan complex

33. Long QT syndrome (LQT) prolonged cardiac repolarization, fatal cardiac arrhythmia Romano-Ward syndrome (by mutations of KCNQ1, CCNH2, KCNE1, KCNE2, KCNJ2, SCN5A or CACNA1C) Jervell and Lange-Nielsen syndrome (by mutations of either KCNQ1 or KCNE1 )

34. Stroke Ischemic stroke (arterial obstruction) and hemorrhagic stroke (breakage) Clustered in family 10% concordance rates in MZ, 5% concordance rates in DZ Causes sickle cell disease MELAS CADASIL by mutations of NOTCH3 blood clotting by deficiencies of protein C and protein S (coagulation inhibitors) by presence of the factor V Leiden allele (a specific mutation of factor V) Risk factors : hypertension, obesity, atherosclerosis, diabetes, and smoking

35. Hypertension Heritability : 20-40% in family, 60% in MZ twins Risk factors: increased sodium intake, decrease physical activity, psychosocial stress, obesity Related components renin-angiotensin system basodilators (nitric oxide, etc) kallikrein-kinin system ion-transport systems Related genes (a very minor proportion) Liddle syndrome by mutations of ENaC epithelial sodium channel Gordon syndrome by mutations of WNK1 or WNK4 kinase genes Major genes not identified yet.

36. Renin- angiotensin- aldosterone system

40. Breast cancer related genes BRCA1, BRCA2 (DNA-repairing genes) TP53 and CHK2: Li-Frameni syndrome BRCA1 kinase gene: ataxia telagiectasia PTEN: Cowden disease MSH2 and MLH1 (DNA-repairing genes): HNPCC risk factors nulliparity, the first child after 30, a high-fat diet, alcohol, estrogen replacement therapy

41. Colon cancer related genes APC tumor suppressor gene six genes responsible for HNPCC STK11 tumor suppressor gene (a kinase): Peutz-Jeghers syndrome, AD SMAD4, BMPRA1, and PTEN: jevenile intestinal polyposis, AD risk factors: a lack of physical activity and a high-fat low-fiber diet

42. Prostate cancer related genes genes in 8q24, highly associated RNASEL gene in 1q: ribonuclease L no high-fat diet, digital examination, prostate-specific antigen test: preventive to tumor promotion

43. Type I diabetes (insulin-dependent diabetes mellitus, IDDM) By T-cell infiltration into the pancreas and destruction of β-cells antibody against β-cells/several HLA class II alleles (HLA- DR3 and/or HLA-DR4) → an autoimmune disorder some cases from specific viral infection Clustered in families siblings of affected individuals: 6% (normal, 0.3-0.5%) affected mother → 1-3% children affected father → 4-6% children between MZ twins → 30-50% between DZ twins → 5-10%

44. Type I diabetes (insulin-dependent diabetes mellitus, IDDM) Genetics 95% of type I diabetes, 50% of normal → HLA-DR3 and/or -DR4 affected parents, a sibling heterozygous HLA-DR3 and -DR4 → 20% absence of ASP57 of DQ chain: 100 times more DM, related to T- cell recognition Related genes variations in a VNTR polymorphism located just 5′ of the insulin gene (11p): 10% of IDDM 20 more candidate genes under investigation CTLA4 (cytotoxic lymphocyte-associated-4) in 2q33, an inhibitory T-cell receptor: DM, rheumatoid arthritis, and celiac disease PTPN22: DM, rheumatoid arthritis and systemic lupus erythematosus

45. Type II diabetes (noninsulin-dependent diabetes mellitusNIDDM) 90% of diabete cases, treatable with controlled diet, oral drugs, exercise (reducing obesity, increasing insulin-sensitivity, and improving glucose tolerance) Clustered in families MZ twin concordance rate: 90% sibling recurrence risk: 10-15% risk factors : a positive family history, obesity Related genes no specific gene found yet (calpain-10, PPAR-γ ?)

46. Maturity onset diabetes of the young (MODY) AD, 1-5% of diabetes cases related genes glucokinase gene HNF1α (hepatocyte nuclear factor 1-α), HNF1β, HNF4α, and IPF1 (insulin promoter factor 1), and NEU-ROD1 (neurogenic differentiation 1)

48. Obesity Body mass index (BMI=wt/ht 2 ): >30 kg/m 2 High risks in heart disease, stroke, type II diabetes Environmentally and genetically related Related genes leptin hormone and its receptor (rare cases) low leptin → increase appetite → obesity mutation of leptin receptor → obesity neuropeptide Y, α-melanocyte-stimulating hormone and receptor, melanocortin-4-receptor (MC4R) : a few cases ․ brain-expressed FTO gene (40% overweight and 70% obesity)

49. Alzheimer disease Characterization of Alzheimer disease progressive dementia and loss of memory the formation of amyloid plaques and neurofibrillary tangles in the brain (cerebral cortex and hippocampus) Clustered in families 10% sibling recurrence risk, some autosomal dominant

50. Alzheimer disease Related genes preseniline 1 (PS1) and preseniline 2 (PS2): early onset disease, involved in cleavage of the amyloid-β precursor protein (APP) by γ-seretase APP in chromosome 21 apolipoprotein E in chromosome 19 APOE4: late onset (at age 75): clearance of amyloid protein α2-macroblobul in chromosome 12: a protease inhibitor interacting with apolipoprotein E low-density lipoprotein receptor-related protein (LRP) in chromosome 12: interacting with apolipoprotein E Difficult for genetic analysis genetic heterogeneity difficult to diagnose late age of onset

51. Cleavage of the amyloid-β precursor protein (APP) by α-secretase

52. Alcoholism Clustered in families DZ twins: 60% Type I a later age of onset introverted, solitary drinkers less clustered in families (heritability 0.21) easily treatable Type II an early age of onset (before age 25) predominant in males extroverted, difficult to treat strongly clustered in families (heritability 0.88) No specific genes found yet GABA receptors ? The related genes may increase susceptibility to alcohol.

53. Schizophrenia a severe emotional disorder by delusions and hallucinations highly clustered in families 8-10% sibling recurrence risk (normal <1%) concordance rate: 47% (MZ), 12% (DZ) related genes dysbindin (DTNBP1, 6p) neuroglobulin 1 (NRG1, 8p) D-amino-acid oxidase activator (G30, 13q) disrupted-in-schizophrenia-1 (DISC1)

55. Bipolar affective disorder manic-depressive disorders (extreme mood swings) More influenced by genetic factors than unipolar disorders (major depression) do. 5-10% sibling recurrence risk (normal <0.5%) bipolar: 79% (MZ), 24% (DZ) unipolar: 54% (MZ), 19% (DZ) Related genes monoamine oxidase A (MAOA) serotonin transporter (5HTT) catechol-O-methyltransferase (COMT) DAOA, NRG1, DISC1, etc.

56. General Principles of Multifactorial Diseases An earlier age of onset → more strongly inherited Bilateral forms → more strongly inherited Some diseases are sex-specific, other diseases are not. Environmental modifications can reduce recurrence risks. Identification of a specific genetic lesion is essential for effective prevention and treatment of genetic disease.