Genetic Analysis of Complex Disease. Группа авторов
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examination of isogenic cell lines with and without the variant for phenotypic changes. These approaches are rapidly evolving, and frequently revised sources, such as Current Protocols in Human Genetics, should be consulted for the latest details on functional studies using these approaches.
Keys to a Successful Study
Foster Interaction of Necessary Expertise
To appropriately carry out any disease gene discovery study, one must use techniques from five different areas of expertise (Figure 1.3). These areas are clinical evaluation, molecular genetics, statistical genetics, bioinformatics, and epidemiology. The first provides the necessary diagnostic and participant recruitment skills needed to define the phenotype and help collect samples and data. The second provides genotyping, sequencing, and functional analysis skills necessary to help locate and identify the genes and variants of interest and evaluate their functional consequences. The third provides the statistical and analytical framework for the proper design of the study and the analysis of the generated data. The fourth provides computational and algorithmic expertise for the processing, storage, and dissemination of large‐scale datasets. And the fifth provides expertise to incorporate environmental variables and apply results at the population level.
The initial focus of gene discovery on single‐gene disorders resulted in a linear approach (Figure 1.1) that could be implemented by a single investigator with expertise in one of these areas, with periodic consultation with colleagues from other disciplines as needed. Complex traits require a multidisciplinary approach that is not easily implemented by a single investigator, and given differences in genetic architecture, available samples, and research questions, different approaches (and thus different teams) may need to be formed for each trait. Thus, experts in each of these fields must be intimately involved in all aspects of the study. Even with all this expertise in place, it is essential that the study not be divided into separate components with little interaction. For example, statistical geneticists and epidemiologists should be involved in the discussion of the clinical phenotype to determine the effect of potential changes to the phenotype definition on the genetic study design, screening approach, and statistical power.
Figure 1.3 Components of a complex disease study and expertise needed to contribute.
Develop Careful Study Design
It may seem self‐evident that a careful study design is necessary for a successful study. However, it is not enough to decide on a general design of “collect cases and controls, genotype on a genome‐wide chip, do GWAS analysis.” Each step in the study requires substantial thought, and the decisions made at one step will have implications for each of the others. Much as a team of engineers and architects must project unintended side effects from a change in a structural design, lest a catastrophic failure ensue, researchers must consider carefully all aspects of the experimental design lest they doom themselves to making inappropriate conclusions based on inadequately obtained and interpreted results.
References
1 Bernstein, F. (1931). Zur grundlegung der chromosomentheorie der vererbung beim menschen. Z. Abst. Vererb. 57: 113–138.
2 Botstein, D., White, R.L., Skolnick, M., and Davis, R.W. (1980). Construction of a genetic linkage map in man using restriction fragment length polymorphisms. Am. J. Hum. Genet. 32 (3): 314–331.
3 Choi, M., Scholl, U.I., Ji, W. et al. (2009). Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Natl Acad. Sci. USA 106 (45): 19096–19101.
4 Corder, E.H., Saunders, A.M., Strittmatter, W.J. et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261 (5123): 921–923.
5 Corder, E.H., Saunders, A.M., Risch, N.J. et al. (1994). Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat. Genet. 7: 180–184.
6 Dewey, F.E., Murray, M.F., Overton, J.D. et al. (2016). Distribution and clinical impact of functional variants in 50,726 whole‐exome sequences from the DiscovEHR study. Science 354 (6319): aaf6814.
7 Edwards, A.O., Ritter, R. 3rd, Abel, K.J. et al. (2005). Complement factor H polymosphism and age‐related macular degeneration. Science 308 (5720): 421–424.
8 Elston, R.C. and Stewart, J. (1971). A general model for the genetic analysis of pedigree data. Hum. Hered. 21: 523–542.
9 Fisher, R.A. (1935a). The detection of linkage with dominant abnormalities. Ann. Eugenics 6: 187–201.
10 Fisher, R.A. (1935b). The detection of linkage with recessive abnormalities. Ann. Eugenics 6: 339–351.
11 Ford, C.E. and Hamerton, J.L. (1956). The chromosomes of man. Nature 178 (4541): 1020–1023.
12 Goate, A., Chartier‐Harlin, M.C., Mullan, M. et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 33: 53–56.
13 Gusella, J.F., Wexler, N.S., Conneally, M.P. et al. (1983). A polymorphic DNA marker genetically linked to Huntington's disease. Nature 306 (5940): 234–238.
14 Haines, J.L., Hauser, M.A., Schmidt, S. et al. (2005). Complement factor H variant increases the risk of age‐related macular degeneration. Science 308 (5720): 419–421.
15 Haldane, J.B.S. and Smith, C.A.B. (1947). A new estimate of the linkage between the genes for color blindness and hemophilia in man. Ann. Eugenics 14: 10–31.
16 Klein, R.J., Zeiss, C., Chew, E.Y. et al. (2005). Complement factor H polymorphism in age‐related macular degeneration. Science 308 (5720): 385–389.
17 Lange, K. and Elston, R.C. (1975). Extension to pedigree analysis. I. Likelihood calculations for simple and complex pedigrees. Hum. Hered. 25: 95–105.
18 Levy‐Lahad, E., Wasco, W., Poorkaj, P. et al. (1995). Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269: 973–977.
19 Manolio, T.A., Collins, F.S., Cox, N.J. et al. (2009). Finding the missing heritability of complex diseases. Nature 461 (7265): 747–753.
20 McKhann, G., Drachman, G., and Folstein, M. (1984). Clinical diagnosis of Alzheimer's disease: report of the NINCDS‐ADRDA Work Group under the auspices of the department of health and human services task force on Alzheimer's disease. Neurology 34: 939–944.
21 Morton, N.E. (1955). Sequential tests for the detection of linkage. Am. J. Hum. Genet. 7: 277–318.
22 Ng, S.B., Turner, E.H., Robertson, P.D. et al. (2009). Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461 (7261): 272–276.
23 Ng, S.B., Buckingham, K.J., Lee, C. et al. (2010). Exome sequencing identifies the cause of a Mendelian disorder. Nat. Genet. 42 (1): 30–35.
24 Ott, J. (1974). Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am. J. Hum. Genet. 26: 588–597.
25 Pericak‐Vance, M.A., Bebout, J.L., Gaskell, P.C. et al. (1991). Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am. J. Hum. Genet. 48 (6): 1034–1050.
26 Risch, N. and Merikangas, K. (1996). The future of genetic studies of complex human disorders. Science 273 (5281): 1516–1517.
27 Rogaev, E.I., Sherrington, R., Rogaeva, E.A. et al. (1995). Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 376 (6543): 775–778.
28 Sadovnick,