Genetics of Common Disorders with Complex Inheritance PDF 2024

Akhobadze Madona M.D., PhD assistant ☺ Genetics of Common Disorders with Complex Inheritance 2024  Content: Qualitative And Quantitative Traits, Twin Studies Genetic And Environmental Modifiers Of Single-Gene Disorders, Examples Of Multifactorial Traits Fo...

Akhobadze Madona M.D., PhD assistant ☺ Genetics of Common Disorders with Complex Inheritance 2024  Content: Qualitative And Quantitative Traits, Twin Studies Genetic And Environmental Modifiers Of Single-Gene Disorders, Examples Of Multifactorial Traits For Which Genetic And Environmental Factors Are Known, The Normal Distribution Reading: Ch. 8 - Thompson & Thompson Genetics in Medicine, Robert L. Nussbaum, Roderick R. McInnes, Seventh Edition  Diseases such as congenital birth defects, myocardial infarction, cancer, mental illness, diabetes, and Alzheimer disease cause morbidity and premature mortality in nearly two of every three individuals during their lifetimes Many of these diseases “run in families”—they seem to recur in the relatives of affected individuals more frequently than in the general population. And yet their inheritance generally does not follow one of the mendelian patterns seen in the single-gene disorders Instead, they are thought to result from complex interactions between a number of genetic and environmental factors and therefore are said to follow a multifactorial (or complex) inheritance pattern. the relatives of an affected individual are more likely to experience the same gene-gene and gene-environment interactions that led to disease in the proband in the first place than are individuals who are unrelated to the proband The multifactorial inheritance pattern that results represents an interaction between the collective effect of the genotype at one or, more commonly, multiple loci (polygenic or multigenic effects) either to raise or to lower susceptibility to disease, combined with a variety of environmental exposures that may trigger, accelerate, exacerbate, or protect against the disease process. QUALITATIVE AND QUANTITATIVE TRAITS complex phenotypes of multifactorial disorders can be divided into two major categories: qualitative and quantitative traits A genetic disease that is either present or absent is referred to as a discrete or qualitative trait; one has the disease or not In contrast are quantitative traits, which are measurable physiological or biochemical quantities such as height, blood pressure, serum cholesterol concentration, and body mass index (a measure of obesity) that underlie many common and devastating illnesses in the population. Genetic Analysis of Qualitative Disease Traits Familial Aggregation of Disease affected individuals may cluster in families - familial aggregation does not mean that a disease must have a genetic contribution families share more than their genes; for example, they often have cultural attitudes and behaviors, socioeconomic status, diet, and environmental exposures in common Concordance and Discordance When two related individuals in a family have the same disease, they are said to be concordant for the disorder. when only one member of the pair of relatives is affected and the other is not, the relatives are discordant for the disease Discordance for phenotype between relatives who share a genotype at loci that predispose to disease can be explained if the unaffected individual has not experienced the other factors (environmental or chance occurrences) necessary to trigger the disease process and make it manifest concordance for a phenotype may occur even when the two affected relatives have different predisposing genotypes, if the disease in one relative is a genocopy or phenocopy of the disease in the other relative. Lack of penetrance and frequent genocopies and phenocopies contribute to obscuring the inheritance pattern in multifactorial genetic disease  Measuring Familial Aggregation in Qualitative Traits Relative Risk λr The familial aggregation of a disease can be measured by comparing the frequency of the disease in the relatives of an affected proband with its frequency (prevalence) in the general population. The relative risk ratio λr is defined as: The subscript r for λ is used here to refer to relatives; in practice, one measures λ for a particular class of relatives, e.g., r = s for sibs, r = p for parents The value of λr is a measure of familial aggregation that depends: both on the risk of the disease’s recurrence in the family and on the population prevalence; the larger λr is, the greater is the familial aggregation A value of λr = 1 indicates that a relative is no more likely to develop the disease than is any individual in the population patients with a disease (the cases) are compared with suitably chosen individuals without the disease (the controls), with respect to family history of disease As well as other factors, such as environmental exposures, occupation, geographical location, parity, and previous illnesses To assess a possible genetic contribution to familial aggregation of a disease, the frequency with which the disease is found in the extended families of the cases (positive family history) is compared with the frequency of positive family history among suitable controls, matched for age and ethnicity, but who do not have the disease Spouses are often used as controls in this situation because they usually match the cases in age and ethnicity and share the same household environment frequently used controls are patients with unrelated diseases matched for age, occupation, and ethnicity  Bias Case-control studies for familial aggregation are subject to many different kinds of errors or bias One of the most troublesome is ascertainment bias, a difference in the likelihood that affected relatives of the cases will be reported to the epidemiologist as compared with the affected relatives of controls A proband’s relatives may be more likely than a control’s relatives to know of other family members with the same or similar disease or may be more motivated to respond to questioning because of familiarity with the disease (recall bias)  Controls should differ from the cases only in their disease status and not in ethnic background, occupation, gender, or socioeconomic status, any of which may distinguish them as being different from the cases in important ways that have little or nothing to do with the fact that they are not affected by the disease Twin Studies monozygotic (MZ) and dizygotic (DZ) “experiments of nature” MZ twins arise from the cleavage of a single fertilized zygote into two separate zygotes early in embryogenesis As a result, MZ twins have identical genotypes at every locus and are always of the same sex. They occur in approximately 0.3% of all births  DZ twins arise from the simultaneous fertilization of two eggs by two sperm; genetically, DZ twins are siblings who share a womb and, like all siblings, share, on average, 50% of the alleles at all loci. DZ twins are of the same sex half the time and of opposite sex the other half DZ twins occur with a frequency that varies as much as 5-fold in different populations from a low of 0.2% among Asians to more than 1% of births in parts of Africa and among African Americans  Disease Concordance in Monozygotic Twins powerful method for determining whether genotype alone is sufficient to produce a particular disease For example, if one MZ twin has sickle cell disease, the other twin will also have sickle cell disease In contrast, when one MZ twin has type 1 diabetes mellitus (previously known as insulin-dependent or juvenile diabetes), only about 40% of the other twins will also have type 1 diabetes Disease concordance less than 100% in MZ twins is strong evidence that nongenetic factors play a role in the disease Such factors could include environmental influences, such as exposure to infection or diet, as well as other effects, such as somatic mutation, effects of aging, and differences in X inactivation in one female twin compared with the other Concordance of Monozygotic Versus Dizygotic Twins MZ and same-sex DZ twins share a common intrauterine environment and sex and are usually reared together in the same household by the same parents Greater concordance in MZ versus DZ twins is strong evidence of a genetic component to the disease This conclusion is strongest for conditions with early onset, such as birth defects. For late-onset diseases, such as neurodegenerative disease of late adulthood, the assumption that MZ and DZ twins are exposed to similar environments throughout their adult lives becomes less valid, and thus a difference in concordance provides less strong evidence for genetic factors in disease causation  Twins Reared Apart If MZ twins are separated at birth and raised apart, geneticists have the opportunity to observe disease concordance in individuals with identical genotypes reared in different environments in research in psychiatric disorders, substance abuse, and eating disorders, in which strong environmental influences within the family are believed to play a role in the development of disease  Study of Obesity Average BMI among MZ or DZ twins was similar, regardless of whether they were reared together or apart correlation for BMI between a pair of twins was much higher for the MZ than the DZ twins the higher correlation between MZ versus DZ twins was independent of whether the twins were reared together or apart which suggests that genotype has a highly significant impact on adult weight and consequently on the risk for obesity and its complications.  Study of alcoholism One of six MZ twin pairs reared apart were concordant for alcoholism a concordance rate at least as high as that seen among MZ twins reared together suggesting that shared genetic factors are far more important than shared environment  Genetic Analysis of Quantitative Traits Measurable physiological quantities, such as blood pressure, serum cholesterol concentration, and body mass index, vary among different individuals and are important determinants of health and disease in the population  The Normal Distribution the mean (μ) and the variance (σ2), The mean is the arithmetic average of the values, and because more people have values for the trait near the average, the curve has its peak at the mean value. The variance (or its square root, the standard deviation, σ), is a measure of the degree of spread of values to either side of the mean and therefore determines the breadth of the curve. Any physiological quantity that can be measured is a quantitative phenotype, with a mean and a variance. The variance of a measured quantity in the population is called the total phenotypic variance  The Normal Distribution graph of the number of individuals in the population (y-axis) having a particular quantitative value (x-axis) produces the familiar bellshaped curve known as the normal (gaussian) distribution  The Normal Range extremely tall or short stature, hypertension, hypercholesterolemia, and obesity are all considered abnormal when a value sits clearly outside the normal range In assessing health and disease in children, height, weight, head circumference, and other measurements are compared with the “normal” expected measurements for a child’s sex and age  Characteristics of Inheritance of Complex Diseases Genes contribute to diseases with complex inheritance, but these diseases are not single-gene disorders and do not demonstrate a simple mendelian pattern of inheritance. Diseases with complex inheritance often demonstrate familial aggregation because relatives of an affected individual are more likely to have disease-predisposing alleles in common with the affected person than are unrelated individuals. Characteristics of Inheritance of Complex Diseases Pairs of relatives who share disease-predisposing genotypes at relevant loci may still be discordant for phenotype (show lack of penetrance) because of the crucial role of nongenetic factors in disease causation. The most extreme examples of lack of penetrance despite identical genotypes are discordant monozygotic twins. The disease is more common among the close relatives of the proband and becomes less common in relatives who are less closely related and therefore share fewer predisposing alleles. Greater concordance for disease is expected among monozygotic versus dizygotic twins  EXAMPLES OF MULTIFACTORIAL TRAITS FOR WHICH GENETIC AND ENVIRONMENTAL FACTORS ARE KNOWN Multifactorial Congenital Malformations Mental Illness Coronary Artery Disease Digenic Retinitis Pigmentosa Venous Thrombosis Hirschsprung Disease Type 1 Diabetes Mellitus Alzheimer Disease Multifactorial Congenital Malformations  Congenital heart defects (CHDs) 4 to 8 per 1000 births five main groups of CHDs can be distinguished: Flow lesions – 50 % Defects in cell migration Defects in cell death Abnormalities in extracellular matrix Defects in targeted growth Relatives of index patients with types of CHDs other than flow lesions can be offered reassurance that their risk is no greater than that of the general population ventricular septal defect overriding aorta pulmonary stenosis right ventricular hypertrophy  Neuropsychiatric Disorders 4% of the human population worldwide Schizophrenia affects 1% of the world’s population. onset commonly in late adolescence or young adulthood abnormalities in thought, emotion, and social relationships associated with delusional thinking and disordered mood MZ concordance in schizophrenia is estimated to be 40% to 60% DZ concordance is 10% to 16% The recurrence risk ratio is elevated in first- and second-degree relatives of schizophrenic patients 22q11 deletion responsible for the velocardiofacial syndrome  Neuropsychiatric Disorders Bipolar disease is predominantly a mood disorder in which episodes of mood elevation, grandiosity, high-risk dangerous behavior, and inflated self-esteem (mania) alternate with periods of depression, decreased interest in what are normally pleasurable activities - anhedonia, feelings of worthlessness, and suicidal thinking prevalence is 0.8% The seriousness of this condition is underscored by the high (10% to 15%) rate of suicide in affected patients MZ twin concordance is 40% to 60% DZ twin concordance is 4% to 8% variable expressivity - classic bipolar illness, depression alone (unipolar disorder), and psychiatric syndrome that involves both thought and mood (schizoaffective disorder)  Coronary Artery Disease (CAD) males are at higher risk for CAD both in the general population and within affected families when the proband is female or young, there is likely to be a greater genetic contribution to MI in the family the recurrence risk in male first-degree relatives of a female proband is sevenfold greater than that in the general population compared with the 2.5-fold increased risk in female relatives of a male proband When the proband is young (A A missense variant in the gene for the clotting factor V Leiden (FVL) (Arg506Gln) A variant in the 3′ untranslated region (UTR) of the gene for the clotting factor prothrombin 20210G>A The use of oral contraceptives (OC) Any venous thrombosis in an individual younger than 50 years Venous thrombosis in unusual sites (such as hepatic, mesenteric, and cerebral veins) Recurrent venous thrombosis Venous thrombosis and a strong family history of thrombotic disease Venous thrombosis in pregnant women or women taking oral contraceptives Relatives of individuals with venous thrombosis younger than 50 years Myocardial infarction in female smokers younger than 50 years  Hirschsprung Disease (HSCR) abnormality of the parasympathetic nervous system in the gut complete absence of some or all of the intrinsic ganglion cells in the myenteric and submucosal plexuses of the colon aganglionic colon is incapable of peristalsis, resulting in severe constipation, symptoms of intestinal obstruction, and massive dilatation of the colon (megacolon) proximal to the aganglionic segment loss-of-function missense or nonsense mutations in the RET gene, which encodes RET, a receptor tyrosine kinase  Hirschsprung Disease (HSCR) 70% isolated birth defect deafness and pigmentary abnormalities of hair and eyes - the Waardenburg-Shah syndrome Patterns of allele sharing among 67 sibpairs concordant for Hirschsprung disease, divided according to the number of loci for which the sibs show allele sharing. The three loci are located at 10q11.2 (RET), 3p21, and 19q12  Type 1 Diabetes Mellitus (T1D) type 1 (insulin dependent; IDDM) and type 2 (non– insulin dependent; NIDDM) Representing about 10% and 88% of all cases differ in typical onset age, MZ twin concordance, and association with particular alleles at the major histocompatibility complex (MHC) Type 1 diabetes has an incidence in the white population of about 1 in 500 (0.2%) but is lower in African and Asian populations  Type 1 Diabetes Mellitus (T1D) It usually manifests in childhood or adolescence. results from autoimmune destruction of the β cells of the pancreas, which normally produce insulin large majority of children who will go on to have type 1 diabetes develop multiple autoantibodies early in childhood against a variety of endogenous proteins, including insulin, well before they develop overt disease concordance among MZ twins is approximately 40%, which far exceeds the 5% concordance in DZ twins  Alzheimer Disease It is the most common cause of dementia in the elderly and is responsible for more than half of all cases of dementia. As with other dementias, patients experience a chronic, progressive loss of memory and other intellectual functions, associated with death of cortical neurons. Age, gender, and family history are the most significant risk factors for AD.  Alzheimer Disease (AD) Once a person reaches 65 years of age, the risk for any dementia, and AD in particular, increases substantially with age and female sex three rare autosomal dominant forms of the disease, in which disease onset is in the third to fifth decade common form of AD with onset after the age of 60 years (late onset). common late-onset AD is APOE - apolipoprotein E - involved in clearing LDL through interaction with high-affinity receptors in the liver, which also binds the Aβ peptide. Chance of remaining unaffected by Alzheimer’s disease as a function of age for different APOE genotypes. At one extreme is the ε4/ε4 homozygote who has a less than 10% chance of remaining free of the disease by the age of 80 years, whereas an ε2/ε3 heterozygote has a more than 80% chance of remaining disease free at the age of 80 years Association of Apolipoprotein E ε4 Allele with Alzheimer Disease* ε3/ε4 heterozygotes have a 40% risk of developing the disease, and ε4/ε4 have a 60% risk by age 85  Genetic Counseling of Families of Patients with Multifactorial Traits The underlying mechanisms by which genes and environment interact to cause diseases with complex inheritance are largely unknown dependent on measuring actual recurrence risks in collections of families to generate average empirical estimates of the recurrence risks the actual risk for an individual family may be larger or smaller than the average population-based empirical risks, although often inadequate, are the only source available for genetic prediction Certain general principles must be considered in providing genetic counseling for multifactorial disorders  The recurrence risk is much higher for first-degree relatives of affected family members than for more distant relatives. The best estimate of the recurrence risk is the empirical risk, which is simply the recurrence risk, observed in similar families, for a relative with the same degree of relationship. It is often useful to state the empirical risk as a multiple of the population risk of the defect. The empirical risk is based entirely on past experience and does not imply that the genetic and environmental factors in the pathogenesis of the malformation are understood. An empirical risk is an average for the population and is not necessarily accurate for a specific family. In general, the recurrence risk is increased by the presence of more than one affected relative; a severe form or an early onset of the disorder; an affected person of the sex less likely to be affected; and consanguineous parentage. For many common disorders with familial aggregation, a minority of cases will be due to single-gene disorders with mendelian inheritance that is masked by small family sizes and incomplete penetrance. გმადლობთ, ყურადღებისთვის!!!