Done by: Hamzah Ayasrah

Topic (5): Multifactorial inheritance

• Traits that result from combined effect of multiple genes are called
polygenic, and when environmental factors also affect them, the term
multifactorial is used.
• Similarly, many adult diseases like hypertension, heart disease, stroke,
diabetes, and some cancers are multifactorial.

The Basic Model

• Multifactorial traits, which are often quantitative (such as blood
pressure), typically show a normal distribution in populations.
• Multifactorial traits, like height and BP, are influenced by multiple
genes following Mendelian inheritance, but also by environmental
factors.
• There’s a correlation between parents’ BPs and those of their children,
due to in part to genes, but also influenced by environmental factors
like diet and stress (family usually shares similar environmental factors).

The threshold model

• Many multifactorial diseases aren't normally distributed but are present
or absent.
• This is explained by a liability threshold model: individuals below the
threshold are unaffected, while those above it express the disease.
• Pyloric stenosis is an example, which is a disorder causing pylorus
narrowing, leads to vomiting, constipation, weight loss, and electrolyte
imbalance in newborns. It may resolve naturally or require surgery.
• Pyloric stenosis is more common in Caucasian males (1/200) than
females (1/1000), the overall prevalence is (3/1000).
• This difference is attributed to a lower disease liability threshold in
males, meaning fewer factors cause the disorder in them.
• Many congenital malformations, including cleft lip/palate, neural tube
defects (anencephaly & spina bifida), club foot (talipes), and some
heart diseases, follow a threshold model.

Recurrence risks and transmission patterns

• For most multifactorial diseases, empirical risks (risks based on
observation of data) are used, this because the number of
contributing genes, parental alleles, and environmental effects are
largely unknown.
• Recurrence risks for multifactorial diseases, unlike single-gene diseases,
vary significantly between populations due to differing gene
frequencies and environmental factors.
• These risks are empirically estimated by studying families with affected
proband (child has the disease) and his relatives.
• The criteria that are used to define multifactorial inheritance:
1. The recurrence risk is higher if more than one family member is
affected.
2. If the expression of the disease in the proband is more severe, the
recurrence risk is higher.
3. The recurrence risk is higher if the proband is of the less commonly
affected sex.
4. The recurrence risk for the disease usually decreases rapidly in
more remotely related relatives.
5. If the prevalence of the disease in a population is f, the risk for
offspring and siblings of probands is approximately √f.

Multifactorial vs Single-Gene inheritance

• Multifactorial diseases result from many genes and environmental
factors, each with small effects.
• In contrast, single-gene diseases like osteogenesis imperfecta need
only one mutation at one of several possible loci to manifest.

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• Some traits, such as height, combine single-gene with large effects,
with a multifactorial background in which genes and environmental
factors have small individual influences.
• Many diseases, like colon, breast, and heart disease, can be caused
by major genes or multiple factors.
• While single-gene inheritance accounts for a small percentage of
cases, identifying these genes is crucial for understanding and treating
the diseases.

Congenital malformations
• Congenital malformations affect about 1/50 of live births.
• Most are multifactorial, with unknown causes in most cases.
• Sibling recurrence risk is typically 1-5%.
• Congenital malformations vary in severity; some, like cleft lip/palate
and pyloric stenosis, are easily repaired, while others, such as neural
tube defects, have more serious consequences.
• Although some malformations occur in absence of other problems,
many are usually associated with other disorders, for example, cleft
lip/palate with trisomy 13, and heart defects with trisomy 13, 18 & 21.

Multifactorial disorders of adult population

Heart disease
• Coronary artery disease (CAD), the most common cause of heart
disease, is caused by atherosclerosis and is influenced by multiple risk
factors including obesity, smoking, hypertension, high cholesterol, and
family history.
• Risk increases with: 1. more affected relatives, 2. if the affected relative
is a female (less affected sex), 3. early onset in relatives (before 55).
• Genetic variations affecting lipoprotein levels, specifically mutations in
the LDL receptor gene (1 in 500) and the apolipoprotein B gene (1 in
1000), significantly raise LDL cholesterol levels, contributing to
atherosclerosis.

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• Modifiable environmental factors like smoking and obesity increase
coronary artery disease (CAD) risk, while exercise and a healthy diet
reduce it.
• A significant drop in US CAD and stroke mortality since 1950 is linked to
reduced smoking, lower saturated fat intake, better healthcare, and
healthier lifestyles.

Hypertension
• Hypertension, a major risk factor for cardiovascular disease, has a 30-
50% heritability, indicating both genetic and environmental influences.
• Environmental factors include high sodium intake, decreased physical
activity, psychosocial stress, and obesity.
• Blood pressure regulation is complex, involving kidney function, ion
transport, vascular tone, and heart function.
• Research focuses on components like the renin-angiotensin system,
vasodilators (nitric oxide, kallikrein-kinin), and ion transport systems
(adducin, sodium-lithium countertransport).
• Genetic studies link hypertension to genes in the renin-angiotensin
system (encoding angiotensinogen, ACE I, angiotensin II receptor I).

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Cancer
• Many common cancers have genetic links; higher recurrence risks are
associated with multiple affected relatives and early-onset disease.
• Specific genes causing inherited cancers (colon, breast, prostate)
have been identified.
• Many major cancers show strong familial clustering due to shared
genes and environmental factors (induce somatic mutations).
• Tobacco use is the most important known cause of cancer,
accounting for about one-third of cases in developed countries.
• Diet, including carcinogenic substances and lack of ‘anticancer’
components (fibers, fruits, vegetables), is another major cause,
potentially accounting for a similar proportion of cases.
• Infectious agents cause approximately 15% of global cancer cases
(HPV, Hepatitis B & C).

Breast cancer
• A woman's breast cancer risk doubles with one affected first-degree
relative, increasing further with more relatives or early-onset cancer in
those relatives (BEFORE 50).
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• Several genes increase hereditary breast cancer risk, most important
are BRCA1 and BRCA2 (involved in DNA repair).
• Other genes like TP53 and CHK2 linked to Li-Fraumeni syndrome, MSH2
linked to Cowden disease, and MLH1 linked to Ataxia telangiectasia,
all predispose to breast cancer.
• Over 90% of breast cancer cases are not inherited.
• Risk factors include nulliparity (infertility), late first pregnancy (after 30),
high-fat diet, alcohol intake, and estrogen replacement therapy.

Colorectal cancer
• Affects 1/20 Americans, with a one-third mortality rate.
• Cluster in families, family history significantly increases risk, two to three
times higher than the general population.
• Genetic mutations in APC tumor suppressor genes or one of DNA
mismatch-repair genes (HNPCC) can cause familial colorectal cancer.
• However, most cases are not inherited and result from a combination
of genetic and environmental factors, such as diet and lack of
exercise, high-fat low-fiber diet.

Prostate cancer
• Prostate cancer risk is increased two-to threefold by a first-degree
relative with the disease; heritability is approximately 40%.
• Late onset (median age 72) complicates genetic analysis, though
genome scans have identified numerous associated polymorphisms.
• Chromosome 8q24 region polymorphisms are linked to prostate and
other cancers, although this region lacks protein-coding genes, it
contains enhancer elements influencing expression of MYC oncogene.
• High-fat diets may increase risk.
• It progresses slowly, so it can be early detected via digital examination
and prostate-specific antigen (PSA) tests which help prevent fatal
metastasis.

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Type 1 Diabetes (insulin dependent)
• Type 1 diabetes, usually diagnosed before age 40, results from the
destruction of insulin-producing beta cells.
• Patients require insulin injections to survive, and the disease is linked to
specific HLA class II alleles and autoantibodies against pancreatic
cells, insulin, and enzymes like glutamic acid decarboxylase.
• Type 1 diabetes has a significantly higher risk among siblings (6% vs 0.3-
0.5% in the general population).
• Recurrence risk increases when there is a diabetic parent, varying by
parent's sex (1-3% for diabetic mothers and 4-6% for diabetic fathers).
• The HLA DR3 and/or DR4 alleles are present in 95% of affected whites,
compared to 50% of the general white population.
• Sibling risk increases to nearly 20% (40 times higher than general
population) if both are heterozygous for DR3/DR4.
• Type 1 diabetes susceptibility is linked to the insulin gene on the short
arm of chromosome 11.
• Allelic variations in a VNTR polymorphism (located 5’ of the insulin
gene) show a strong risk association with the disease.
• Differences in the number of VNTR repeats affect insulin gene
transcription and contributing to differing susceptibility levels.
• Inherited genetic variations in this insulin region account for about 10%
of type 1 diabetes family clustering.

Type 2 Diabetes (non-insulin dependent)

• Type 2 diabetes, comprising over 90% of diabetes cases, is rapidly
increasing, affecting 10-20% of adults in developed countries.
• Patients have some degree of insulin production, but it involves insulin
resistance and obesity, often treatable with diet and/or medication.
• Usually seen in >40 years patients, but prevalence is increasing in
adolescents and young adults due to rising obesity.
• shows higher recurrence risks (15-40%) in first-degree relatives
compared to type 1 diabetes.
• The most important risk factors are family history and obesity (increases
insulin resistance).

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• Over 70 genes influencing type 2 diabetes susceptibility have been
found, with TCF7L2, encoding an insulin-secreting transcription factor,
being the most significant.

Maturity-onset Diabetes of the Young (MODY)

• Accounts for 1% to 5% of all diabetes cases, usually appearing before
age 25 and inherited as autosomal dominant.
• It is not linked to obesity.
• Glucokinase gene mutations account for about half of MODY cases,
which is a rate-limiting enzyme converting glucose to glucose-6-
phosphate in pancreas.
• Another 40% of cases are due to mutations in any of five genes for
transcription factors involved in pancreatic development or insulin
regulation—hepatocyte nuclear factor-1a, -1β, -4a (HNF1α, HNF1β,
HNF4α), insulin promoting factor-1 (IPF1), and neurogenic
differentiation-1 (NEUROD1).

Obesity
• Obesity's global prevalence is rising sharply, a significant portion of
adults in America and Britain are overweight or obese, increasing their
risk for heart disease, stroke, type 2 diabetes, and certain cancers.
• Obesity shows strong heritability; adoption studies demonstrate a
correlation between adoptees' weight and their biological parents',
not adoptive parents'.
• Fatness heritability is around 0.5 (measured by skinfold thickness), with
genes for leptin and its receptor implicated.
• Leptin, a hormone secreted by adipocytes, regulates appetite by
interacting with the hypothalamus.
• High leptin levels signal satiety, while low levels increase appetite.
• Leptin interacts with other appetite control components like
neuropeptide Y and a-melanocyte-stimulating hormone and its
receptor melanocortin-4 (MC4R).
• Mutations in the MC4R gene are present in 3-5% of severely obese
people.
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Alzheimer’s disease
• Affects 10% of the population over 65, and 40% of population over 85.
• It's characterized by dementia, memory loss, and the formation of
amyloid plaques and neurofibrillary tangles in the brain (cerebral
cortex and hippocampus), causing neuronal loss and death within 7-
10 years of symptom onset.
• Family history doubles the risk, while 3-5% of cases are early-onset
(before 65) and often inherited in autosomal dominant fashion and
show familial clustering.
• Autosomal dominant genes account for about 10% of Alzheimer's
disease cases.
• Genetically heterogeneous, at least four genes linked to AD
susceptibility have been identified.
• Three of these genes (encoding presenilin-1, -2, and amyloid-β
precursor protein) affect the cleavage and processing of amyloid
precursor protein, causing early-onset AD.
• The fourth gene, associated with late-onset AD, encodes
apolipoprotein E.

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