Multifactorial disease

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Multifactorial diseases are not confined to any specific pattern of single gene inheritance and are likely to be caused when multiple genes come together along with the effects of environmental factors. [1]

Contents

In fact, the terms 'multifactorial' and 'polygenic' are used as synonyms and these terms are commonly used to describe the architecture of disease causing genetic component. [2] Multifactorial diseases are often found gathered in families yet, they do not show any distinct pattern of inheritance. It is difficult to study and treat multifactorial diseases because specific factors associated with these diseases have not yet been identified. Some common multifactorial disorders include schizophrenia, diabetes, asthma, depression, high blood pressure, Alzheimer's, obesity, epilepsy, heart diseases, Hypothyroidism, club foot, cancer, birth defects and even dandruff.

The multifactorial threshold model [3] assumes that gene defects for multifactorial traits are usually distributed within populations.  Firstly, different populations might have different thresholds. This is the case in which occurrences of a particular disease is different in males and females (e.g. Pyloric stenosis). The distribution of susceptibility is the same but threshold is different. Secondly, threshold may be same but the distributions of susceptibility may be different. It explains the underlying risks present in first degree relatives of affected individuals.

Characteristics

Multifactorial disorders exhibit a combination of distinct characteristics which are clearly differentiated from Mendelian inheritance.

Risk Factors

The risk for multifactorial disorders is mainly determined by universal risk factors. Risk factors are divided into three categories; genetic, environmental and complex factors (for example overweight).

Genetic risk factors are associated with the permanent changes in the base pair sequence of human genome. In the last decade, many studies have been generated data regarding genetic basis of multifactorial diseases. Various polymorphism have been shown to be associated with more than one disease, examples include polymorphisms in TNF-a, TGF-b and ACE genes, as well as mutations in BRCA1. BRCA2, BARD1, and BRIP1. [6] [7] [8] [9]

Environmental risk factors vary from events of life to medical interventions. The quick change in the patterns of morbidity, within one or two generations, clearly demonstrates the significance of environmental factors in the development and reduction of multifactorial disorders. [10] Environmental risk factors include change in life style (diet, physical activity, stress management) and medical interventions (surgery, drugs).

Many risk factors originate from the interactions between genetic and environmental factors and referred as complex risk factors. Examples include epigenetic changes, body weight, pollution, and plasma cortisol level. [11]

Multifactorial Disorders; Continuous or Discontinuous

Autosomal or sex-linked single gene conditions generally produce distinct phenotypes, said to be discontinuous: the individual either has the trait or does not. However, multifactorial traits may be discontinuous or continuous.[ citation needed ]

Continuous traits exhibit normal distribution in population and display a gradient of phenotypes while discontinuous traits fall into discrete categories and are either present or absent in individuals. It is interesting to know that many disorders arising from discontinuous variation show complex phenotypes also resembling continuous variation [12] This occurs due to the basis of continuous variation responsible for the increased susceptibility to a disease. According to this theory, a disease develops after a distinct liability threshold is reached and severity in the disease phenotype increases with the increased liability threshold. On the contrary, disease will not develop in the individual who does not reach the liability threshold. Therefore, an individual either having disease or not, the disease shows discontinuous variation.[ citation needed ]

An example of how the liability threshold works can be seen in individuals with cleft lip and palate. Cleft lip and palate is a birth defect in which an infant is born with unfused lip and palate tissues. An individual with cleft lip and palate can have unaffected parents who do not seem to have a family history of the disorder.[ citation needed ]

History

Francis Galton was the first scientist who studied multifactorial diseases and was the cousin of Charles Darwin. Major focus of Galton was on 'inheritance of traits' and he observed "blending" characters. [13] The average contribution of each several ancestor to the total heritage of the offspring [14] and is now known as continuous variation. When a trait (human height) exhibiting continuous variation is plotted against a graph, the majority of population distribution is centered around the mean. [15] Galton's work is contrary to work done by Gregor Mendel; as the latter studied "nonblending" traits and kept them in different categories. [16] The traits exhibiting discontinuous variation, occur in two or more distinct forms in a population as Mendel found in color of petals.[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Genetic disorder</span> Health problem caused by one or more abnormalities in the genome

A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.

The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a specific gene depends on the number of copies of each chromosome found in that species, also referred to as ploidy. In diploid species like humans, two full sets of chromosomes are present, meaning each individual has two alleles for any given gene. If both alleles are the same, the genotype is referred to as homozygous. If the alleles are different, the genotype is referred to as heterozygous.

<span class="mw-page-title-main">Heredity</span> Passing of traits to offspring from the species parents or ancestor

Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic information of their parents. Through heredity, variations between individuals can accumulate and cause species to evolve by natural selection. The study of heredity in biology is genetics.

<span class="mw-page-title-main">Mendelian inheritance</span> Type of biological inheritance

Mendelian inheritance is a type of biological inheritance following the principles originally proposed by Gregor Mendel in 1865 and 1866, re-discovered in 1900 by Hugo de Vries and Carl Correns, and later popularized by William Bateson. These principles were initially controversial. When Mendel's theories were integrated with the Boveri–Sutton chromosome theory of inheritance by Thomas Hunt Morgan in 1915, they became the core of classical genetics. Ronald Fisher combined these ideas with the theory of natural selection in his 1930 book The Genetical Theory of Natural Selection, putting evolution onto a mathematical footing and forming the basis for population genetics within the modern evolutionary synthesis.

<span class="mw-page-title-main">Penetrance</span> Proportion of individuals that express the trait associated with a gene variant

Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation that exhibit clinical symptoms among all individuals with such mutation. For example: If a mutation in the gene responsible for a particular autosomal dominant disorder has 75% penetrance, then 75% of those with the mutation will go on to develop the disease, showing its phenotype, whereas 25% will not. 

A quantitative trait locus (QTL) is a locus that correlates with variation of a quantitative trait in the phenotype of a population of organisms. QTLs are mapped by identifying which molecular markers correlate with an observed trait. This is often an early step in identifying the actual genes that cause the trait variation.

<span class="mw-page-title-main">Human behaviour genetics</span> Field that examines the role of genetic and environmental influences on human behaviour

Human behaviour genetics is an interdisciplinary subfield of behaviour genetics that studies the role of genetic and environmental influences on human behaviour. Classically, human behavioural geneticists have studied the inheritance of behavioural traits. The field was originally focused on determining the importance of genetic influences on human behaviour. It has evolved to address more complex questions such as: how important are genetic and/or environmental influences on various human behavioural traits; to what extent do the same genetic and/or environmental influences impact the overlap between human behavioural traits; how do genetic and/or environmental influences on behaviour change across development; and what environmental factors moderate the importance of genetic effects on human behaviour. The field is interdisciplinary, and draws from genetics, psychology, and statistics. Most recently, the field has moved into the area of statistical genetics, with many behavioural geneticists also involved in efforts to identify the specific genes involved in human behaviour, and to understand how the effects associated with these genes changes across time, and in conjunction with the environment.

Genetic architecture is the underlying genetic basis of a phenotypic trait and its variational properties. Phenotypic variation for quantitative traits is, at the most basic level, the result of the segregation of alleles at quantitative trait loci (QTL). Environmental factors and other external influences can also play a role in phenotypic variation. Genetic architecture is a broad term that can be described for any given individual based on information regarding gene and allele number, the distribution of allelic and mutational effects, and patterns of pleiotropy, dominance, and epistasis.

<span class="mw-page-title-main">Human genetics</span> Study of inheritance as it occurs in human beings

Human genetics is the study of inheritance as it occurs in human beings. Human genetics encompasses a variety of overlapping fields including: classical genetics, cytogenetics, molecular genetics, biochemical genetics, genomics, population genetics, developmental genetics, clinical genetics, and genetic counseling.

In genetics, expressivity is the degree to which a phenotype is expressed by individuals having a particular genotype. Alternatively, it may refer to the expression of a particular gene by individuals having a certain phenotype. Expressivity is related to the intensity of a given phenotype; it differs from penetrance, which refers to the proportion of individuals with a particular genotype that share the same phenotype.

A polygene is a member of a group of non-epistatic genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance, a type of non-Mendelian inheritance, as opposed to single-gene inheritance, which is the core notion of Mendelian inheritance. The term "monozygous" is usually used to refer to a hypothetical gene as it is often difficult to distinguish the effect of an individual gene from the effects of other genes and the environment on a particular phenotype. Advances in statistical methodology and high throughput sequencing are, however, allowing researchers to locate candidate genes for the trait. In the case that such a gene is identified, it is referred to as a quantitative trait locus (QTL). These genes are generally pleiotropic as well. The genes that contribute to type 2 diabetes are thought to be mostly polygenes. In July 2016, scientists reported identifying a set of 355 genes from the last universal common ancestor (LUCA) of all organisms living on Earth.

<span class="mw-page-title-main">Gene–environment interaction</span> Response to the same environmental variation differently by different genotypes

Gene–environment interaction is when two different genotypes respond to environmental variation in different ways. A norm of reaction is a graph that shows the relationship between genes and environmental factors when phenotypic differences are continuous. They can help illustrate GxE interactions. When the norm of reaction is not parallel, as shown in the figure below, there is a gene by environment interaction. This indicates that each genotype responds to environmental variation in a different way. Environmental variation can be physical, chemical, biological, behavior patterns or life events.

Genetic association is when one or more genotypes within a population co-occur with a phenotypic trait more often than would be expected by chance occurrence.

<span class="mw-page-title-main">Threshold model</span> Type of mathematical model

In mathematical or statistical modeling a threshold model is any model where a threshold value, or set of threshold values, is used to distinguish ranges of values where the behaviour predicted by the model varies in some important way. A particularly important instance arises in toxicology, where the model for the effect of a drug may be that there is zero effect for a dose below a critical or threshold value, while an effect of some significance exists above that value. Certain types of regression model may include threshold effects.

Genetic epidemiology is the study of the role of genetic factors in determining health and disease in families and in populations, and the interplay of such genetic factors with environmental factors. Genetic epidemiology seeks to derive a statistical and quantitative analysis of how genetics work in large groups.

<span class="mw-page-title-main">Neurogenetics</span> Study of role of genetics in the nervous system

Neurogenetics studies the role of genetics in the development and function of the nervous system. It considers neural characteristics as phenotypes, and is mainly based on the observation that the nervous systems of individuals, even of those belonging to the same species, may not be identical. As the name implies, it draws aspects from both the studies of neuroscience and genetics, focusing in particular how the genetic code an organism carries affects its expressed traits. Mutations in this genetic sequence can have a wide range of effects on the quality of life of the individual. Neurological diseases, behavior and personality are all studied in the context of neurogenetics. The field of neurogenetics emerged in the mid to late 20th century with advances closely following advancements made in available technology. Currently, neurogenetics is the center of much research utilizing cutting edge techniques.

Behavioural genetics, also referred to as behaviour genetics, is a field of scientific research that uses genetic methods to investigate the nature and origins of individual differences in behaviour. While the name "behavioural genetics" connotes a focus on genetic influences, the field broadly investigates the extent to which genetic and environmental factors influence individual differences, and the development of research designs that can remove the confounding of genes and environment. Behavioural genetics was founded as a scientific discipline by Francis Galton in the late 19th century, only to be discredited through association with eugenics movements before and during World War II. In the latter half of the 20th century, the field saw renewed prominence with research on inheritance of behaviour and mental illness in humans, as well as research on genetically informative model organisms through selective breeding and crosses. In the late 20th and early 21st centuries, technological advances in molecular genetics made it possible to measure and modify the genome directly. This led to major advances in model organism research and in human studies, leading to new scientific discoveries.

Addiction vulnerability is an individual's risk of developing an addiction during their lifetime. There are a range of genetic and environmental risk factors for developing an addiction that vary across the population. Genetic and environmental risk factors each account for roughly half of an individual's risk for developing an addiction; the contribution from epigenetic risk factors to the total risk is unknown. Even in individuals with a relatively low genetic risk, exposure to sufficiently high doses of an addictive drug for a long period of time can result in an addiction. In other words, anyone can become an individual with a substance use disorder under particular circumstances. Research is working toward establishing a comprehensive picture of the neurobiology of addiction vulnerability, including all factors at work in propensity for addiction.

A human disease modifier gene is a modifier gene that alters expression of a human gene at another locus that in turn causes a genetic disease. Whereas medical genetics has tended to distinguish between monogenic traits, governed by simple, Mendelian inheritance, and quantitative traits, with cumulative, multifactorial causes, increasing evidence suggests that human diseases exist on a continuous spectrum between the two.

<span class="mw-page-title-main">Complex traits</span>

Complex traits are phenotypes that are controlled by two or more genes and do not follow Mendel’s Law of Dominance. They may have a range of expression which is typically continuous. Both environmental and genetic factors often impact the variation in expression. Human height is a continuous trait meaning that there is a wide range of heights. There are an estimated 50 genes that affect the height of a human. Environmental factors, like nutrition, also play a role in a human’s height. Other examples of complex traits include: crop yield, plant color, and many diseases including diabetes and Parkinson's disease. One major goal of genetic research today is to better understand the molecular mechanisms through which genetic variants act to influence complex traits. Complex Traits are also known as polygenic traits and multigenic traits.

References

[9] [4]

  1. ↑ Duarte, Christine W.; Vaughan, Laura K.; Beasley, T. Mark; Tiwari, Hemant K. (2013), "Multifactorial Inheritance and Complex Diseases", Emery and Rimoin's Principles and Practice of Medical Genetics, Elsevier, pp. 1–15, doi:10.1016/b978-0-12-383834-6.00014-8, ISBN   978-0-12-383834-6, S2CID   160734530
  2. ↑ Plomin, Robert; Haworth, Claire M. A.; Davis, Oliver S. P. (2009-10-27). "Common disorders are quantitative traits". Nature Reviews Genetics. 10 (12): 872–878. doi:10.1038/nrg2670. ISSN   1471-0056. PMID   19859063. S2CID   13789104.
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  4. 1 2 The Children's Hospital of Philadelphia. (2014, August 24). Multifactorial inheritance and birth defects. Children's Hospital of Philadelphia. https://www.chop.edu/conditions-diseases/multifactorial-inheritance-and-birth-defects
  5. ↑ Korf, Bruce R.; Sathienkijkanchai, Achara (2009), "Introduction to Human Genetics", Clinical and Translational Science, Elsevier, pp. 265–287, doi:10.1016/b978-0-12-373639-0.00019-4, ISBN   978-0-12-373639-0
  6. ↑ Sayed-Tabatabaei, F.A.; Oostra, B.A.; Isaacs, A.; van Duijn, C.M.; Witteman, J.C.M. (2006-05-12). "ACE Polymorphisms". Circulation Research. 98 (9): 1123–1133. doi: 10.1161/01.res.0000223145.74217.e7 . ISSN   0009-7330. PMID   16690893.
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  10. ↑ Pereira, Mark A; Kartashov, Alex I; Ebbeling, Cara B; Van Horn, Linda; Slattery, Martha L; Jacobs, David R; Ludwig, David S (January 2005). "Fast-food habits, weight gain, and insulin resistance (the CARDIA study): 15-year prospective analysis". The Lancet. 365 (9453): 36–42. doi:10.1016/s0140-6736(04)17663-0. ISSN   0140-6736. PMID   15639678. S2CID   205941559.
  11. ↑ Scherer, Stephen (2005-08-01). "Faculty of 1000 evaluation for Epigenetic differences arise during the lifetime of monozygotic twins". doi: 10.3410/f.1026838.326638 .{{cite journal}}: Cite journal requires |journal= (help)
  12. ↑ Carpenter, Geoffrey (December 1982). "Copeland, John G. et al. Telemundo: A Basic Reader. New York: Random House, Inc., 1980; Freeman, G. Ronald. Intercambios: An Activities Manual. New York: Random House, Inc., 1980Copeland, John G. et al. Telemundo: A Basic Reader. New York: Random House, Inc., 1980. Pp. 264.Freeman, G. Ronald. Intercambios: An Activities Manual. New York: Random House, Inc., 1980. Pp. 209". Canadian Modern Language Review. 38 (2): 361a–362. doi:10.3138/cmlr.38.2.361a. ISSN   0008-4506.
  13. ↑ "The average contribution of each several ancestor to the total heritage of the offspring". Proceedings of the Royal Society of London. 61 (369–377): 401–413. 1897-12-31. doi: 10.1098/rspl.1897.0052 . ISSN   0370-1662.
  14. ↑ "The average contribution of each several ancestor to the total heritage of the offspring". Proceedings of the Royal Society of London. 61 (369–377): 401–413. 1897-12-31. doi: 10.1098/rspl.1897.0052 . ISSN   0370-1662.
  15. ↑ Mossey, P. A. (June 1999). "The Heritability of Malocclusion: Part 1—Genetics, Principles and Terminology". British Journal of Orthodontics. 26 (2): 103–113. doi:10.1093/ortho/26.2.103. ISSN   0301-228X. PMID   10420244.
  16. ↑ Olby, Robert C. (October 2000). "Horticulture: the font for the baptism of genetics". Nature Reviews Genetics. 1 (1): 65–70. doi:10.1038/35049583. ISSN   1471-0056. PMID   11262877. S2CID   1896451.
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