Genes, Environment, and Common Genes, Environment, and Common DiseasesDiseases

Chapter 5Chapter 5

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Disease in PopulationsDisease in Populations Incidence rateIncidence rate

Number of new cases of a disease reported during Number of new cases of a disease reported during a specific period (typically 1 year) divided by the a specific period (typically 1 year) divided by the number of individuals in the populationnumber of individuals in the population

Prevalence ratePrevalence rate Proportion of the population affected by a disease Proportion of the population affected by a disease

at a specific point in timeat a specific point in time

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Risk FactorsRisk Factors Relative riskRelative risk

Incidence rate of a disease among individuals Incidence rate of a disease among individuals exposed to a risk factor divided by the incidence exposed to a risk factor divided by the incidence rate of a disease among individuals rate of a disease among individuals notnot exposed exposed to a risk factor to a risk factor

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Multifactorial InheritanceMultifactorial Inheritance PolygenicPolygenic

Variation in traits caused by the effects of multiple Variation in traits caused by the effects of multiple genesgenes

Multifactorial traitMultifactorial trait Variation in traits caused by genetic and Variation in traits caused by genetic and

environmental or lifestyle factors environmental or lifestyle factors Quantitative traitsQuantitative traits

Traits that are measured on a continuous numeric Traits that are measured on a continuous numeric scalescale

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Multifactorial InheritanceMultifactorial Inheritance Threshold modelThreshold model

Liability distributionLiability distribution Threshold of liabilityThreshold of liability

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Multifactorial InheritanceMultifactorial Inheritance

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Multifactorial InheritanceMultifactorial Inheritance

Characteristics of multifactorial disordersCharacteristics of multifactorial disorders Result from hereditary and environmental Result from hereditary and environmental

factorsfactors Hereditary component is polygenicHereditary component is polygenic

• Individual involved genes follow mendelian principlesIndividual involved genes follow mendelian principles• Many genes act together to influence the expressed Many genes act together to influence the expressed

traittrait

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Multifactorial InheritanceMultifactorial Inheritance

Concordance and discordanceConcordance and discordance ConcordanceConcordance

• Expression of the disease in two related family Expression of the disease in two related family membersmembers

DiscordanceDiscordance• Expression of the disease in one family member but Expression of the disease in one family member but

not a secondnot a second

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Multifactorial InheritanceMultifactorial Inheritance

Twin studies and concordanceTwin studies and concordance Genetic conditionsGenetic conditions

• Monozygotic (MZ) twins: 100% concordanceMonozygotic (MZ) twins: 100% concordance

• Dizygotic (DZ) twins: less than 100% and similar to Dizygotic (DZ) twins: less than 100% and similar to that among other siblingsthat among other siblings

Environmental conditionsEnvironmental conditions• Equal concordance rates among MZ and DZ twinsEqual concordance rates among MZ and DZ twins

Multifactorial conditionsMultifactorial conditions• MZ twins with greater concordance than DZ twins, but MZ twins with greater concordance than DZ twins, but

rates are not 100%rates are not 100%

Adoption studiesAdoption studies Gene-environment-lifestyle interactionGene-environment-lifestyle interaction

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Recurrence RisksRecurrence Risks Recurrence risks of multifactorial diseases Recurrence risks of multifactorial diseases

can change substantially because gene can change substantially because gene frequencies as well as environment and frequencies as well as environment and lifestyle factors can differ among populationslifestyle factors can differ among populations

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Recurrence RisksRecurrence Risks Recurrence risk becomes higher if more than Recurrence risk becomes higher if more than

one family member is affectedone family member is affected If the expression of the disease in the If the expression of the disease in the

proband is more severe, recurrence risk is proband is more severe, recurrence risk is higherhigher

Recurrence risk is higher if the proband is of Recurrence risk is higher if the proband is of the less commonly affected sexthe less commonly affected sex

Recurrence risk for the disease usually Recurrence risk for the disease usually decreases rapidly in remotely related decreases rapidly in remotely related relativesrelatives

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Nature and NurtureNature and Nurture NatureNature

GeneticsGenetics NurtureNurture

Environment-lifestyleEnvironment-lifestyle

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Nature and NurtureNature and Nurture Twin studiesTwin studies

Monozygotic (identical) Monozygotic (identical) Dizygotic (fraternal)Dizygotic (fraternal) Concordant traitConcordant trait

• Both members of a twin pair share a traitBoth members of a twin pair share a trait

Discordant traitDiscordant trait• A twin pair does not share a traitA twin pair does not share a trait

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Nature and NurtureNature and Nurture Adoption studiesAdoption studies

Children born to parents who have a disease but Children born to parents who have a disease but are then subsequently adopted by parents lacking are then subsequently adopted by parents lacking the disease are studied for the recurrence of the the disease are studied for the recurrence of the diseasedisease

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Genetics of Common DiseasesGenetics of Common Diseases Congenital malformationsCongenital malformations

Congenital diseases are present at birth or shortly Congenital diseases are present at birth or shortly after birthafter birth

Most congenital diseases are multifactorialMost congenital diseases are multifactorial

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Adult Multifactorial DiseasesAdult Multifactorial Diseases Coronary heart diseaseCoronary heart disease

Potential mycocardial infarction caused by Potential mycocardial infarction caused by atherosclerosisatherosclerosis

Risk increases if:Risk increases if:• There are more affected relativesThere are more affected relatives• Affected relatives are female rather than maleAffected relatives are female rather than male• Age of onset is younger than 55 yearsAge of onset is younger than 55 years

Autosomal dominant familial Autosomal dominant familial hypercholesterolemia, high-fat diet, lack of hypercholesterolemia, high-fat diet, lack of exercise, smoking, and obesity exercise, smoking, and obesity

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Familial HypercholesterolemiaFamilial Hypercholesterolemia

Autosomal dominantAutosomal dominant 1 in 500 is heterozygous for FH gene; 1 in 1 1 in 500 is heterozygous for FH gene; 1 in 1

million is homozygous for the traitmillion is homozygous for the trait Serum cholesterol 300 to 400 mg/dl in Serum cholesterol 300 to 400 mg/dl in

heterozygote; 600 to 1200 mg/dl in heterozygote; 600 to 1200 mg/dl in homozygotehomozygote

Cholesterol deposits in arteries and skin Cholesterol deposits in arteries and skin (xanthomas)(xanthomas)

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Familial HypercholesterolemiaFamilial Hypercholesterolemia

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HypertensionHypertension Risk factor for heart disease, stroke, and Risk factor for heart disease, stroke, and

kidney diseasekidney disease 20% to 40% of blood pressure variations are 20% to 40% of blood pressure variations are

genetic; this means that 60% to 80% are genetic; this means that 60% to 80% are environmentalenvironmental

Causes of hypertensionCauses of hypertension Sodium intake, lack of exercise, stress, obesity, Sodium intake, lack of exercise, stress, obesity,

smoking, and high-fat intakesmoking, and high-fat intake

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Breast CancerBreast Cancer Affects 12% of American women who live to 85Affects 12% of American women who live to 85 If a woman has a first-degree relative with If a woman has a first-degree relative with

breast cancer, her risk doublesbreast cancer, her risk doubles Recurrence risk increases if age of onset in the Recurrence risk increases if age of onset in the

affected relative is early and if the cancer is affected relative is early and if the cancer is bilateralbilateral

An autosomal dominant form (5%) has been An autosomal dominant form (5%) has been linked to chromosomes 13 and 17 linked to chromosomes 13 and 17

Other genes are implicatedOther genes are implicated

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Colorectal CancerColorectal Cancer 1 in 20 Americans will develop colorectal 1 in 20 Americans will develop colorectal

cancercancer Second only to lung cancerSecond only to lung cancer

Risk factorsRisk factors Genetics Genetics High-fat and low-fiber diet are contributorsHigh-fat and low-fiber diet are contributors

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DiabetesDiabetes

Leading cause of blindness, heart disease, Leading cause of blindness, heart disease, and kidney failureand kidney failure

Two major typesTwo major types Type 1 (insulin-dependent diabetes mellitus)Type 1 (insulin-dependent diabetes mellitus) Type 2 (nonType 2 (non––insulin-dependent diabetes mellitus)insulin-dependent diabetes mellitus)

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Type 1 DiabetesType 1 Diabetes

Autoimmune destruction of insulin-producing Autoimmune destruction of insulin-producing beta cells in the pancreasbeta cells in the pancreas T cell activation and autoantibody productionT cell activation and autoantibody production

Onset before 40 years of ageOnset before 40 years of age Higher incidence with offspring of diabetic Higher incidence with offspring of diabetic

fathersfathers Recurrence riskRecurrence risk

0.55 MZ twin concordance rate0.55 MZ twin concordance rate 1% to 6% sibling recurrence1% to 6% sibling recurrence

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Type 2 DiabetesType 2 Diabetes 80% to 90% of all diabetes cases80% to 90% of all diabetes cases Neither HLA nor autoantibodies commonly Neither HLA nor autoantibodies commonly

seen in type 2seen in type 2 Person has insulin resistance or diminished Person has insulin resistance or diminished

insulin productioninsulin production Risk factorsRisk factors

High carbohydrate diet and obesityHigh carbohydrate diet and obesity Recurrence riskRecurrence risk

0.90 MZ twin concordance rate0.90 MZ twin concordance rate 10% to 15% sibling recurrence10% to 15% sibling recurrence

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ObesityObesity Body mass index >30Body mass index >30

BMI = W/HBMI = W/H22 (weight in kg and height in meters) (weight in kg and height in meters) Obesity is a substantial risk factor for heart Obesity is a substantial risk factor for heart

disease, stroke, and type 2 diabetesdisease, stroke, and type 2 diabetes Adoptive studiesAdoptive studies

Body weights of adopted individuals correlated Body weights of adopted individuals correlated significantly with their natural parents’ body significantly with their natural parents’ body weightsweights

Twin studiesTwin studies Higher concordance in MZ twins than DZ twinsHigher concordance in MZ twins than DZ twins

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Alzheimer DiseaseAlzheimer Disease Progressive dementia and loss of memoryProgressive dementia and loss of memory Formation of amyloid plaques and Formation of amyloid plaques and

neurofibrillary tangles in the brainneurofibrillary tangles in the brain Risk of developing AD doubles in individuals Risk of developing AD doubles in individuals

who have an affected first-degree relativewho have an affected first-degree relative Mutations in any of three genes that affect Mutations in any of three genes that affect

amyloid-beta depositionamyloid-beta deposition Presenilin 1 (PS1)Presenilin 1 (PS1) Presenilin 2 (PS2)Presenilin 2 (PS2) Amyloid-beta precursor protein gene (APP)Amyloid-beta precursor protein gene (APP)

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AlcoholismAlcoholism Risk is 3 to 5 times higher in individuals with Risk is 3 to 5 times higher in individuals with

an alcoholic parentan alcoholic parent Adoption studies Adoption studies

Offspring of nonalcoholic parents, when reared by Offspring of nonalcoholic parents, when reared by alcoholic parents, did not have an increased riskalcoholic parents, did not have an increased risk

Twin studiesTwin studies Concordance ratesConcordance rates

• MZ: >60%MZ: >60%

• DZ: <30%DZ: <30%

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Psychiatric DisordersPsychiatric Disorders SchizophreniaSchizophrenia

Severe emotional disorder characterized by Severe emotional disorder characterized by delusions, hallucinations, and bizarre, withdrawn, delusions, hallucinations, and bizarre, withdrawn, or inappropriate behavioror inappropriate behavior

Recurrence risk among the offspring of one Recurrence risk among the offspring of one affected parent is 10 times higher than the general affected parent is 10 times higher than the general populationpopulation

Twin and adoption studies indicate that genetic Twin and adoption studies indicate that genetic factors are likely to be involvedfactors are likely to be involved

Bipolar affective disorderBipolar affective disorder GeneticsGenetics Minimal environmental influenceMinimal environmental influence