Pharmacogenetics of Mood Disorders: Is there a Future?
Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen in Handbook of Depression and Anxiety, 2003
Classical genetics of human disease deals with monogenic disorders in which a single mutation in a single gene is causatively related to the phenotype. The genetics of complex illnesses such as diabetes, hypertension, coronary artery disease, and most of the major psychiatric disorders do not fit this simple paradigm. The same distinction is applicable to pharmacogenetics. Genetic factors that underlie pharmacokinetic effects and influence drug bioavailability (such as the effect of CYP2D6 polymorphism on the metabolism of a variety of psychotropic and other drugs, which is inherited as an autosomal recessive trait) may be monogenic [17]. For the most part, however, pharmacogenetic traits are likely to be polygenic and multifactorial. A polygenic trait is one that is influenced by a number of different genes, each of which contributes a portion of the effect and may do so additively as well as interactively (epistasis). The term multifactorial indicates that both genetic and environmental factors contribute substantially and variably to the phenotype.
Common disorders and genetic counselling
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
The terms ‘multifactorial’ or ‘polygenic’ are frequently used to describe the genetic basis underlying the great majority of common disorders where there is no clear Mendelian pattern. Of the two terms, multifactorial is the more appropriate since it recognises that these disorders are the result of both environmental and genetic factors and does not prejudge the relative role of either category. ‘Polygenic’ means that many different genetic loci are involved, and usually implies that there is a very large number of such factors involved, each being of very small effect, and that their influences combine in a straightforward fashion. In fact, for many diseases where the ‘genetic architecture’ of disease susceptibility has been examined, there is rather a spectrum of genetic factors ranging from rare genetic variants of large effect, through a moderate number of genetic variants of lesser but still substantial effect (sometimes known as ‘oligogenes’), to a multitude of genetic variants of small or very small effect. Very little is known about the way these factors interact. It is often simply assumed that they interact in regular, predictable patterns (with relative risks being combined multiplicatively, as if they were independent) because the research that would be needed to measure the complex interactions between the different factors would be so demanding.
Basic genetics and patterns of inheritance
Hung N. Winn, Frank A. Chervenak, Roberto Romero in Clinical Maternal-Fetal Medicine Online, 2021
In multifactorial inheritance, it is postulated that genetic influences from both parents, in combination with environmental factors, lead to a specific birth defect or disorder. In polygenic inheritance, multiple genetic influences in combination act together to produce a disorder. Examples of birth defects with multifactorial inheritance include isolated congenital heart defects, cleft lip with or without cleft palate, cleft palate, neural tube defects, pyloric stenosis, and congenital dislocation of the hips (Table 4). In multifactorial disorders, there is no evidence to suggest simple Mendelian inheritance. For example, the defect does not necessarily appear in sequential generations of a family, as would an autosomal dominant condition due to a single-gene mutation. However, there may be clustering of the defect in more than one member of a pedigree. The appearance of multifactorial disorders has been explained by a threshold model in which certain genes present in an individual, along with prenatal environmental factors, accumulate toward a threshold. If an individual has enough of these genes and factors, a threshold will be crossed and the defect will appear (32).
Congenital fibrinogen disorder caused by digenic mutations of the FGA and FGB genes
Published in Hematology, 2020
Xiong Wang, Ning Tang, Na Shen, Yanjun Lu, Dengju Li
For some disorders, the discovery of rare genetic variants and the observation of familial co-segregation in some cases result in the perception that Mendelian inheritance may apply. However, recent advances in genetic tests have revealed several disorders beyond the One Gene-One Disease paradigm, indicatinga more complex inheritance and pleiotropy in heritable disorders [13]. Cerrone et al., reported that oligogenic or polygenic genetic variants contributed to inheritable cardiac disorders [14]. Monogenic, polygenic, and oligogenic inheritance were found in familial hypercholesterolemia [15]. In polygenic or oligogenic inheritance, one variant may function as genetic modifiers determining the ultimate disease manifestations. Kuuluvainen et al., reported that the penetrance of SOD1 p.Ala90Val mutation was modulated by other variants, indicating oligogenic basis of sporadic ALS [16]. Within bleeding, thrombotic and platelet disorders, Downes et al., reported 3.9% and 1.8% patients harbored oligogenic variants for the thrombotic and coagulation classes in a large cohort in UK recently [17]. This is the first time we have identified oligogenic mutations of the FGA and FGB genes for CFD in Chinese.
Human height: a model common complex trait
Published in Annals of Human Biology, 2023
Mitchell Conery, Struan F. A. Grant
Adding individuals of non-European ancestry to capture the missing 5–10% of common SNP-based heritability in these populations should improve the accuracy of polygenic scores in non-European populations by allowing for discovery of disease associated variants that are rare in Europeans but common in other groups (Wojcik et al. 2019; Bentley et al. 2020). Increasing diversity is a necessary step for ensuring that polygenic prediction techniques work well for all people and should be a goal for future research in height as in other complex traits. In addition to benefiting polygenic scores and variant discovery, building cohorts of greater diversity should also enable future studies to more precisely fine-map putative causal variants by leveraging differing patterns of linkage disequilibrium across ancestries; cohorts of African ancestry with their smaller haplotype blocks are especially useful in this regard (Hutchinson et al. 2020; Lu Z et al. 2022; Yuan et al. 2023). There are several large-scale ongoing efforts including All of Us (The “All of Us” Research Program 2019), the Million Veterans Program (Gaziano et al. 2016), and H3Africa (Owolabi et al. 2019) that aim to recruit participants from these underrepresented ancestry-groups. These efforts clearly should continue and even expand.
How have our clocks evolved? Adaptive and demographic history of the out-of-African dispersal told by polymorphic loci in circadian genes
Published in Chronobiology International, 2018
Arcady A. Putilov, Vladimir B. Dorokhov, Michael G. Poluektov
More general hypothetical reason for correlation between latitude and allele frequency showed by some of loci in reference genes might be sufficient interconnections of the gene regulatory networks that were yielded by the analysis of genetic background of complex traits. All genes expressed in a given cell are liable to affect the functions of core trait-related genes. Therefore, most heritability can be explained by effects on genes outside core pathways (Boyle et al. 2017). Some of polymorphisms in reference genes might be involved in such indirect way in regulation of either chronobiological traits or skin pigmentation or some other traits that were shaped to more or less extent by the latitude-driven polygenic selection. Moreover, it cannot be fully excluded that latitude-dependent environmental factors played, at least, secondary role in selection of complex traits associated with these genes.
Related Knowledge Centers
- Diabetes
- Epistasis
- Mendelian Inheritance
- Phenotype
- Quantitative Genetics
- Quantitative Trait Locus
- Pleiotropy
- Gene
- NON-Mendelian Inheritance
- Last Universal Common Ancestor