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11 Comments on the Utility of Social Science Surveys for the Discovery and Validation of Genes Influencing Complex Traits--Harald H.H. Göring
11 Comments on the Utility of Social Science Surveys for the Discovery and Validation of Genes Influencing Complex Traits--Harald H.H. Göring
Pages 208-230
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From page 208... ...
At the present time, the emphasis is clearly on the importance of genetic factors. The popular press contains daily reports of the discovery of yet another gene influencing yet another 208
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I start with a brief overview of the nature of so-called complex traits and highlight some of the concepts behind study designs that are being used for the identification of genes. I attempt to contrast the traits for which gene-mapping studies have succeeded and the designs of gene discovery experiments to social science surveys, with a focus of the suitability of the latter for gene identification.
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Not all components are equally important. genotype at major gene 1 penetrance detectance genotypes at individual other major environment genes phenotype genotypes at family polygenes environment cultural factors FIGURE 11-1 Schematic of the etiological architecture of a prototypical complex trait.
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From page 211... ...
, no such correlation structure exists for the environmental factors, such that it is not possible to investigate all components of the environment. The investigator thus has to decide beforehand which aspects of the environment are to be measured, and for many complex traits knowledge of which environmental factors may be relevant is inadequate.
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From page 212... ...
The power of a gene-mapping study is a function of the detectance (Weiss and Terwilliger, 2000) , and a key goal of designing a powerful study is to select a design in which the observed phenotype predicts the underlying trait locus genotype as accurately as possible, that is, P(genotype|phenotype)
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From page 213... ...
that all affected individuals harbor the same underlying genetic defect, that is, there is a one-to-one relationship of disease and causal gene. Hence, the detectance within a family is very high, and linkage analysis should succeed in gene localization.
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. For the analysis of complex traits, however, it is not clear whether the founding populations were of sufficiently small size to simplify the allelic architecture to such a degree to make it tractable for genetic dissection (Hovatta et al., 1998, 1999)
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It may also be advantageous to collect families that are densely loaded with affected individuals. The presence of multiple cases in a family generally increases the probability that genetic factors are a major determinant when compared with singleton individuals with the condition
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Alternatively, one may obtain information on exposure to known risk factors and account for them by statistical means, such as by adjusting a quantitative trait for the effects of, say, sex, age, and other variables of known importance. This approach can also be used to account for previously identified genetic risk factors (Blangero et al., 1999; Martin et al., 2001)
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From page 217... ...
For example, while cardiovascular disease is highly complex, such that the existence of a "stroke gene" or a "heart attack gene" that explains most of these events in the general population is unlikely, many risk factors for cardiovascular disease are known -- such as blood pressure, various cholesterol subfractions, inflammatory markers, oxidative stress markers, blood clotting
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Besides the concepts discussed above, many additional strategies may be pursued in collecting samples for complex trait gene mapping. The common logic behind these approaches is to make the genetic etiology tractable.
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From page 219... ...
In addition, the fact that a sample ascertained on a specific phenotype is different from the wider population is not crucial, because, even in randomly ascertained samples, it is nearly impossible to simultaneously identify genetic factors and estimate their effect size, because of what is sometimes referred to as the winner's curse. Complex trait gene-mapping studies tend to have fairly low power.
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From page 220... ...
In an effort to localize major genetic factors influencing the expression levels of individual transcripts, we performed genome-wide variance components-based linkage analysis (Amos, 1994; Almasy and Blangero, 1998)
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NOTE: The figure shows the maximum lod score (obtained in variance componentsbased linkage analysis across the autosomal chromosomes) as a function of the estimated heritability for the expression levels of 19,648 autosomal transcripts.
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. Nonetheless, most samples failed to yield a significant lod score in genome-wide linkage analysis, and the few lod score peaks that exceeded the threshold of 3 were inconsistent between the different samples.
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GÖRING 223 SOCIAL SCIENCE SURVEYS: A TOOL FOR GENE DISCOVERY OR VALIDATION? The etiological complexity of multifactorial traits poses an enormous challenge for efforts to localize and identify the underlying genes.
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However, even if complete sequence data were available for all 300 million U.S. residents or even all 6 billion humans on earth, the identification of causal genetic factors influencing human behaviors and similarly complex traits would still be very challenging.
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While social science surveys may in principle be useful for validating previously identified genetic variants, survey cohorts are by no means universally useful for that purpose, nor are they the only or necessarily the best type of sample available for replication. In many instances, investigations of the genetic etiology of human traits are conducted by many research groups simultaneously, either in collaboration or in competition with one another.
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From page 226... ...
And while large surveys can in principle be used for validation of specific genetic variants by association analysis, these cohorts will often not be useful for replicating findings of heritability or linkage, which require information on familial relationships that are missing from many social science surveys. If social science surveys are to be used for gene validation, two conditions must be met: The phenotype of interest must have been assessed in the survey, and DNA samples must have been collected.
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This chapter has focused mostly on the potential utility of social science surveys for complex trait gene discovery and validation. However, social science and biological or genetic research obviously influence and aid each other in a myriad of ways.
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American Journal of Human Genetics, 70(3)
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. Localization of genetic factors influencing height by genome-wide linkage analysis in large pedigree samples.
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. Power of variance component linkage analysis to detect quantitative trait loci.
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