Genetic Analysis of Complex Disease. Группа авторов
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J.M. (1981). Genetic disease in the offspring of older fathers. Obstet. Gynecol. 57 (6): 745–749.
8 Garrod, A.E. (1902). The incidence of alkaptonuria: a study in chemical individuality. Lancet ii: 1616–1620.
9 Hamosh, A., Fitz‐Simmons, S.C., Macek, M. et al. (1998). Comparison of the clinical manifestations of cystic fibrosis in black and white patients. J. Pediatr. 132: 255–259.
10 Hardy, G.H. (1908). Mendelian proportions in a mixed population. Science 28: 41–50.
11 Hoogerwaard, E., van der Wouw, P., Wilde, A. et al. (1999). Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy. Neuromuscul. Disord. 9: 347–351.
12 Jorde, L.B., Carey, J.C., and White, R.L. (eds.) (1995). Medical Genetics. St. Louis, MO: C. W. Mosby.
13 Koenig, M., Monaco, A.P., and Kunkel, L.M. (1988). The complete sequence of dystrophin predicts a rod‐shaped cytoskeletal protein. Cell 53: 219–228.
14 La Spada, A. and Taylor, J. (2010). Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat. Rev. Genet. 11: 247–258.
15 Penrose, L.S. (1955). Parental age and mutation. Lancet ii: 312–313.
16 Pericak‐Vance, M.A. and Haines, J.L. (1995). Genetic susceptilbility to Alzheimer disease. Trends Genet. 11: 504–508.
17 Polak, U., McIvor, E., Dent, S.Y. et al. (2013). Expanded complexity of unstable repeat diseases. Biofactors 39 (2): 164–175.
18 Ratjen, F. and Doring, G. (2003). Cystic fibrosis. Lancet 361 (9358): 681–689.
19 Rousseau, F., Bonaventure, J., Legeai‐Mallet, L. et al. (1994). Mutations in the gene encoding fibroblast growth factor receptor‐3 in achondroplasia. Nature 371: 252–254.
20 Saunders, A.M., Strittmatter, W.J., Schmechel, D. et al. (1993). Association of apolipoprotein E allele epsilon 4 with late‐onset familial and sporadic Alzheimer’s disease. Neurology 43: 1467–1472.
21 Shiang, R., Thompson, L.M., Zhu, Y.‐Z. et al. (1994). Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78: 335–342.
22 Stankiewicz, P. and Lupski, J. (2010). Structural variation in the human genome and its role in disease. Annu. Rev. Med. 61: 437–455.
23 Stoll C, Roth M‐P, Bigel P (1982): A reexamination of parental age effect on the occurrence of new mutations for achondroplasia. Prog. Clin. Biol. Res., 104:419–426.
24 Strachan, T. and Read, A.P. (1996). Human Molecular Genetics, 1ste. New York: Wiley.
25 Takeshima, Y., Yagi, M., Okizuka, Y. et al. (2010). Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center. J. Hum. Genet. 55: 379–388.
26 Thompson, M.W., McInnes, R.R., Willard, H.F., and Thompson, J.S. (eds.) (1991). Genetics in Medicine, 5the. Philadelphia, PA: W. B. Saunders Company.
27 Tjio, J.H. and Levan, A. (1956). The chromosome number of man. Hereditas 42: 1–6.
28 Turner, G., Webb, T., Wake, S., and Robinson, H. (1996). Prevalence of fragile X syndrome. Am. J. Med. Genet. 64 (1): 196.
29 Watson, J.D. (1968). The Double Helix. New York: Atheneum.
30 Watson, J.D. and Crick, F.H.C. (1953). A structure for deoxyribose nucleic acid. Nature 171: 737–738.
31 Weinberg, W. (1908). Uber den nachweis der vererbung beim Menschen. Jahreshefte des vereins fur vaterlandische naturkunde in wurttemberg. Wurttemberg 64: 368–382.
32 Zarrei, M., MacDonald, J.R., Merico, D., and Scherer, S.W. (2015). A copy number variation map of the human genome. Nat. Rev. Genet. 16 (3): 172–183.
3 Determining the Genetic Component of a Disease
Allison Ashley Koch1 and Evadnie Rampersaud2
1 Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA
2 Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN, USA
Introduction
Genetics is believed to contribute to the etiology of almost every human trait and condition. Even for infectious diseases that have been traditionally described as environmental, such as tuberculosis and HIV, genetic factors have been implicated either in the susceptibility to infection or in the severity of the condition (Bellamy 1998; Hill 1999; Bellamy et al. 2000; Gonzalez et al. 2001; Shields and Dell 2001). Understanding the role of genetics in disease etiology can allow development of successful therapies that improve the quality of life for affected individuals and their families. However, before embarking on expensive and labor‐intensive studies to identify the genetic factors involved in a particular condition, one should evaluate the evidence that genes contribute to that trait or condition.
For Mendelian disorders, such as sickle cell anemia, cystic fibrosis, and Duchenne muscular dystrophy, establishing a role for genetics is straightforward. These conditions have predictable, recognizable inheritance patterns, and their primary etiologies can be attributed to variations in single genes. The phenotypic expression of the condition is highly correlated with the genotype at the disease locus. For example, all individuals who carry two copies of the Hb S variant of the β‐globin gene are affected with sickle cell anemia (Neel 1949). While there is variation in the severity of the symptoms, all individuals who are homozygous for Hb S will exhibit some symptoms of the disorder. In contrast, complex disorders, such as cardiovascular disease, cancers, and psychiatric disorders, usually do not display distinct inheritance patterns. Such disorders have a significant genetic component but are caused by an intricate web of genetic and environmental interactions. As a result, establishing a role for genetics in the etiology of complex disorders can be more difficult. While the genotype at a single locus may contribute to the susceptibility to develop a condition, it is expected that other loci are involved, as well. That is, multiple loci may be interacting with each other or the environment to contribute to disease. Moreover, different loci may be contributing to disease susceptibility in different families. A classic example of a complex disease susceptibility gene is the association between the APOE locus and Alzheimer disease. Corder et al. (1993) demonstrated that individuals who carry the four allele of the APOE locus have a higher risk and earlier age of onset for late onset Alzheimer disease when compared with individuals who do not carry the four allele. Furthermore, this association is dose‐dependent. Individuals who have two copies of APOE‐4 are at greater risk for the condition than individuals who carry one copy of APOE‐4. Some Alzheimer families carry the APOE‐4 genotype and some do not. Thus, the APOE gene alone does not explain the etiology of the disease. In addition to the diminished correlation between genotype and phenotype, due to the high frequency of complex diseases in the general population, often one cannot be certain that two individuals within a family have developed the condition as a result of the same genetic liability or genetic heritability. For example, the family may exhibit bilineality (family history is present on both the maternal and paternal side). Consequently, each side of the family may contribute different genetic susceptibilities to the condition. Even in the absence of bilineality, there are complications. Some individuals in the family may express the condition as a result of exposure to an environmental insult. Therefore, it can be quite challenging to determine which family members carry the same genetic susceptibilities. For all these reasons, it is more difficult to establish a genetic basis for a complex disease than for a Mendelian disease.
However, even in the presence of such complexities, there are methods available to evaluate whether or not genetics plays an important role in the disease etiology. Those methods are the primary topic of this chapter and should be explored prior to embarking on more elaborate analyses such as genome‐wide association analyses or linkage analyses. Importantly, before considering any analysis,