Multifactorial diseases human diseases are caused by multiple causes genetic environmental or both.Some disease genetic predominate like Down syndrome and some environmental like infections (viruses).Most chronic diseases are caused by both (schizophrenia and diabetes ancongenetal malformation

Genotype + environmental = phenotype polygenic trait (two or more genes determine it) multifactor traits are controlled by two or more genes and also interact with environment.

-most human traits are polygenic.

Polygenic inheritance (when a single trait is controlled by two or more sets of alleles) **inheritance and expression of a phenotype being determined by many genes at different loci each gene exert a small additive effect **additive effect >> the effects of genes are cumulate no one gene is dominant or recessive to another genes are rarely acted alone environmental factors and other genes may modify expression.Traits are: mandolin: single genepolygenic: multiple genes multifactor (Complex): interaction between gene and environment.

…..Complex trait: cumulative effect of genes and the influence of environment.Polygenic traits: Controlled by one or more genes and pattern of inheritance can be measured quantitavely.Multifactor traits: result from interaction of two or more genes and one or more environmental factor.…..Phenotypes are influences by many genes and also by environment.Two types of phenotype.A.Discontinous: phenotype that can be fall into two or more distinct no overlapping classes..

Discontinuous traits - For example, if we cross a tall and short pea plant and look at F2 plants, we know the genotype of short plants, and we can give a generalized genotype for the tall plant phenotype. Furthermore, if we know the genotype we could predict the phenotype of the plant. These types of phenotypes are called discontinuous traits and fall into discrete classes - eg.either tall or short.  B.continous: phenotype that is distributed from one extreme to another in an overlapping fashion

Continuous traits - Other traits do not fall into discrete classes. Rather, when a segregating population is analyzed, a continuous distribution of phenotypes is found. An example is ear length in corn. Black Mexican Sweet corn has short ears, whereas Tom Thumb popcorn has long ears. When these two inbred lines are crossed, the length of the F1 ears

are intermediate to the two parents. Furthermore, when the F1 plants are intermated, the distribution of ear length in the F2 ranges from the short ear Black Mexican Sweet size to the Tom Thumb popcorn size. The distribution resembles the bell-shaped curve for a normal distribution. ……… *when the number of genes which are controlling the trait increase the number of phenotype classes increase.………polygenic traits are continuous not discrete and the effect of gene is additive or synergistic and its quantities trait loci and the genes which are involved may have major or minor impacts. (Height, hair color, body weight, cholesterol levels, IQ) skin color: is phenotype interaction between pigment gene and environment, melanin production result in skin pigmentation and also protects skin from UV radiation. In genetic sense race based on skin color has little meaning and 93% of genetic traits are equally frequent among all people.

Eye Color: eye color genes are UN known and analysis revealed many genes. ** Mice have more than 60 eye color genes.

………

Multifactorial inheritance:

The type of hereditary pattern seen when there is more than one genetic factor involved and, sometimes, when there are also environmental factors participating in the causation of a condition.

Many common traits are multifactorial. Skin color, for example, is multifactorially determined. So is height and so also is intelligence.

The most common diseases tend also to multifactorial. Type 2 diabetes, the most common type of diabetes, is multifactorial. It is due to the inheritance of susceptibility genes (genes that make one susceptible to developing diabetes) plus environmental factors such as obesity. Obesity, in turn, clearly is multifactorial in causation.** They show familial clustering and determined by the additive effects of many genes at different loci (each gene controlling the trait contribute a small amount to the phenotype) with the effect of environment (interact with the genotype to produce the phenotype) the variation of expression are due to environmental factors. What are the factors that increase the probability of recurrence in a particular family??1. More than one member of the family is affected.2. Severty or early onset disease.3. High heritability of disorder4.close relationship to proband. (A term used most often in medical genetics and other medical fields to denote a particular subject (person or animal) being studied or reported on) * Male or female *.one sex may be affected more than other sex**multifactorial conditions have an unequal sex ratio.5. proband of more rarely affected sex.

The chance of this trait to happen again depends upon how close the family member with the trait is related to you if your brother and sister higher chance than if your cousin is affected.(Examples of disorders of multifactorial inheritance)*Congenital malformation: heart defect neural tube defectscleft lip/palate.Pyloric stenosis congenital hip dysplasia

*common non-communicable diseases: asthma schizophreniaDMhypertension

Multifactorial inheritance as a mode of inheritance for condition is more likely if:

• Condition is relatively common

• Incidence in relatives lower than for single gene disorder but higher than in general population

• Risks to sibs similar to that of children

• Incidence falls rapidly in more distant relatives

• Incidence in relatives rises as the manifestations become more severe in the index case

• Risk to relatives higher when index case is of the least commonly affected sex

• Observed risk rises following the birth of two affected children

(Refer to the slides) liability –threshold model

All of the factors that influence the development of a multifactorial disorder whether genetic or environmental can be considered as a single entity known as liability

.(**The threshold model was first applied to behavior by Irving Gottesman and James Shields in their classic twin study of schizophrenia. They postulated that a number of different genes along with a number of environmental variables acted as risk and protective factors for the development of schizophrenia. When enough risk factors accumulate and greatly outweigh the protective factors, then schizophrenia may develop. Because many factors contribute to schizophrenia, the liability or predisposition or vulnerability towards schizophrenia is really a continuous, quantitative

dimension. Once, however, that liability (or predisposition or vulnerability) passes a certain point (the threshold), then a discrete phenotype emerges (affected with schizophrenia versus unaffected with schizophrenia).

The liabilities of all people form a continuous variable and have a normal distribution in both general population and relatives of affected individuals.The incidence of the condition is greatest among relatives of the most severely affected patients.

The risk is greatest among close relatives and decreases rapidly in more distant relatives.

The incidence of the condition is greatest among relatives of the most severely affected patients.

If there is more than one affected close relative then the risks for other relatives are increased

Liability = quantitative trait that presents a genetic risk for a threshold trait

Individuals with a liability above threshold develop the trait

The risk of manifesting a threshold trait has H2 and h2 that cannot be estimated directly, but can be inferred from the incidents of the trait among individuals and their relatives

(Refer to the slides) # (30 -34)

Analyzing multifactorial traits: it's difficult and requires multiple techniques they use human genome sequences, population and family studies.

Empiric risk – incidence or rate an event occurs in a population. (The chance that a disease will occur in a family,

based on experience with the diagnosis, past history, and

medical records rather than theory.)

Prevalence - proportion of the population that has a disorder at a specific time. (The proportion of individuals in a population having a disease or characteristic. Prevalence is a statistical concept referring to the number of cases of a disease that are present in a particular population at a given time, whereas incidence refers to the number of new cases that develop in a given period of time).

Empiric Risk – increases with the severity, more family members affected and the closer the relationship to an affected individual.

• The closer the relationship; increased probability, since increase in genes in common.

• Based on observations so it can be used even in difficult transmission patterns.( based on observation not study because we don’t know that one gene that we should study)

Heritability- Measurement of genetic.( How much of this condition is related to genetic factor)

• Blood relationship and the coefficient of relatedness (genes 2 related people share.

• Designate 10, 20,30

• Pedigrees (a document to record ancestry, used by genealogists in study of human family lines, and in selective breeding of animals)

50 % chance of inheriting genes from parents and between siblings

Empiric risks:

• Recurrence risks are empiric risks derived from population studies. So they are observational and do not depend on theory as the Mendelian characters.

• Empiric risks vary according to several factors.

1- The incidence of the condition isgreatest among relatives of the mostseverely affected patients** Presumably because they are the most extreme deviants along the liability curve. For example, in cleft lip/palate the proportion of affected first-degree relatives (parents, siblings, and offspring) is 6% if the index patient has bilateral cleft lip and palate, but only 2% if the index patient has a unilateral cleft lip

( fe jadwal bl slides ) #38

2- Recurrence risk increases with increasing number of previously affected children

•** If a couple have a baby with neural tube defect, recurrence risk is about 2-4%. If they have 2 children with neural tube defects, the recurrence risk rises to 10%. It is not that having a second baby caused their recurrence risk to increase, but it makes them a couple who always had been at a high risk. For MF disorders, bad luck in the past is a predictor of bad luck in the future.

3- The risk is greatest among close relatives of the index case and decreases rapidly in more distant relatives

**In spina bifida the risks to first-, second- and third degree relatives of the index case are approximately 4%, 1% and less than 0.5%, respectively.

Heritability (H) – Genetic Component

• Estimates the proportion of the phenotypic variation in a population due to genetic differences

– Value between 0 and 1: higher number = greater genetic component

• Differs from Empiric Risk (includes environmental component)

– Both vary with environment and time – different reasons

• Estimated from: proportion of those showing trait/those expected to show trait

•4- If the condition is more common in individuals of one particular sex, recurrence risk varies according to sex of index case** If the condition is more common in individuals of one sex, then relatives of an affected individual of the less frequently affected sex will be at higher risk than relatives of an affected individual of the more frequently affected sex. This is illustrated by the condition pyloric stenosis. Pyloric stenosis shows a male to female ratio of 5 to 1.

( the threshold must be higher for girls than boys )Relatives of an affected girl must have a higher Susceptibility than relatives of an affected boy.

Offspring of male index patients are 6.4% risk for sons and 2.5% risk for daughters. The risks to the offspring of female index patients are 22.9% for sons and 11.4% for daughters.……….. Heritability Measures the Genetic Contribution to Phenotypic Variation** Heritability is measured by estimating the relative contributions of genetic and non-genetic differences to the total phenotypic variation in a population. Heritability is an important concept in quantitative genetics, particularly in selective breeding and behavior genetics (for instance, twin studies), but is less widely used in population genetics.

** Heredity has nothing to do with incidence in population** (mesh eza Kan el heritability 3ali m3nato

incidence kteer) Slides 45-46

……………………… Analyzing multifactorial traits:

**Comparisons between and within families

Twins dizygotic and monozygotic

Twins raised apart ( same gene different environment)

Adopted children(different gene same environment )

**Association studies – compare SNP patterns between affected and unaffected groups, identify important DNA regions

• Concordance (( the presence of the same trait in both members of a pair of twins. However, the strict definition is the probability that a pair of individuals will both have a certain characteristic, given that one of the pair has the characteristic. For example, twins are concordant when both have or both lack a given trait.[1]The ideal example of concordance is that of identical twins.))

• Used to determine heritability

• Has limitations, assumes both type of twins share similar environments

• MZ twins often share more similar environments

• Monozygotic twins

Single fertilization

Genetically identical

• Dizygotic twins

Independent fertilizations

Share approximately half their genes

Twin studies ** reveal the absolute and relative importance of environmental and   genetic   influences on individuals in a sample. Twin research is considered a key tool in   behavioral genetics   and in content fields, from biology to psychology. Twin studies are part of the methods used in   behavior genetics , which includes all data that are genetically informative – siblings ,   adoptees , pedigree data etc.

………..slide 50 for calculation of relative risk of disease association.

………..

Slides 51-52

Concordance % of pairs of individuals that share the trait (both affected or both unaffected)

Fe jadwal bl slides shofo.

Separating genes and environment :

• Dizygotic twins: Shared environment and 50% of genes

• Monozygotic twins:Identical genotype, and shared environmen

• Twins raised apart: Shared genotype but not environment

• Adopted individuals: Shared environment but not genes

• Disease concordance less than 100% in MZ twins is strong evidence that non-genetic factors play a role in the disease.

• Greater concordancy in MZ versus DZ twins is strong evidence of a genetic component to the disease.

• An important exception is X-linked diseases. In females, discordancy could also be due to differences in the proportion of maternal versus paternal X that is inactivated.

Ascertainment bias can also affect twin studies

(refer to the slides 55-56)

……..

Correlation : Correlation coefficient

The fraction of genes shared by two relatives

Identical twins have 100% of their genes in common (correlation coefficient = 1.0)

When raised in separate environments identical twins provide an estimate of the degree of environmental influence on gene expression

Association Studies : Studies which compare a group of interest (cases)

to a control group for the presence of a gene or SNP.

Controls are matched to cases for characteristics that may confound results: age, ethnicity, gender, environment.

If the SNP is present more often in cases than controls, it is associated with the trait and implies that the SNP may be near a gene impacting the trait.

SNP (single nucleotide polymorphism) :Nucleotide site with more than one allele is a polymorphism

• On average between two random individuals, there is one SNP every 1000 bases => 3 million differences!

Genetic linkage and linkage analysis :** Genetic linkage analysis is a powerful tool to detect the chromosomal location of disease genes. It is based on the observation that genes that reside physically close on a chromosome remain linked during meiosis. For most neurologic diseases for which the underlying biochemical defect was not known, the identification of the chromosomal location of the disease gene was the first step in its eventual isolation. By now, genes that have been isolated in this way include examples from all types of neurologic diseases, from neurodegenerative diseases such as Alzheimer, Parkinson, or ataxias, to diseases of ion channels leading to periodic paralysis or hemiplegic migraine, to tumor syndromes such as neurofibromatosis types 1 and 2.

Two loci are linked if they appear closseby in the same chromosome.

The task of linkage analysis is to find markers that are linked to the hypothetical disease locus

Complex diseases in focus ® usually need to search for one gene at a time

Requires mathematical modelling of meiosis

• One of the two main approaches in gene mapping.

Uses pedigree data

Farah Ode'h