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2 results

  • Chapter 22 - Alcoholism

  • Edited by John I. Nurnberger, Jr, Wade Berrettini, University of Pennsylvania School of Medicine
  • Book:
    Principles of Psychiatric Genetics
    Published online:
    05 October 2012
    Print publication:
    13 September 2012, pp 279-286

  • Summary

    All of the major linkage studies relied on the qualitative diagnosis of autism for their analysis. Their results strongly suggest that individual common genetic risk factors are not likely to cause the entire core deficits required for the broad diagnosis of autism or autism spectrum disorders (ASD). Thus, it is necessary to define more precise intermediate phenotypes or endophenotypes that comprise components of the disorder that might be more closely related to a few single genes of small effect size. Endophenotypes are heritable traits characteristic of the disorder and are present in relatives of affected individuals more frequently than in the unrelated general population. The vast majority of association studies have involved the assessment of single candidate genes whose selection was based either on biological hypotheses or on published linkage regions. Similar to other complex genetic diseases, identifying significant genome-wide linkage and association signals in autism has been challenging.

  • Hypothesis-driven candidate genes for schizophrenia compared to genome-wide association results

  • A. L. Collins, Y. Kim, P. Sklar, International Schizophrenia Consortium, M. C. O'Donovan, P. F. Sullivan
  • Journal:
    Psychological Medicine / Volume 42 / Issue 3 / March 2012
    Published online by Cambridge University Press:
    19 August 2011, pp. 607-616
  • Background

    Candidate gene studies have been a key approach to the genetics of schizophrenia (SCZ). However, the results of these studies are confusing and no genes have been unequivocally implicated. The hypothesis-driven candidate gene literature can be appraised by comparison with the results of genome-wide association studies (GWAS).

    Method

    We describe the characteristics of hypothesis-driven candidate gene studies from the SZGene database, and use pathway analysis to compare hypothesis-driven candidate genes with GWAS results from the International Schizophrenia Consortium (ISC).

    Results

    SZGene contained 732 autosomal genes evaluated in 1374 studies. These genes had poor statistical power to detect genetic effects typical for human diseases, assessed only 3.7% of genes in the genome, and had low marker densities per gene. Most genes were assessed once or twice (76.9%), providing minimal ability to evaluate consensus across studies. The ISC studies had 89% power to detect a genetic effect typical for common human diseases and assessed 79% of known autosomal common genetic variation. Pathway analyses did not reveal enrichment of smaller ISC p values in hypothesis-driven candidate genes, nor did a comprehensive evaluation of meta-hypotheses driving candidate gene selection (SCZ as a disease of the synapse or neurodevelopment). The most studied hypothesis-driven candidate genes (COMT, DRD3, DRD2, HTR2A, NRG1, BDNF, DTNBP1 and SLC6A4) had no notable ISC results.

    Conclusions

    We did not find support for the idea that the hypothesis-driven candidate genes studied in the literature are enriched for the common genetic variation involved in the etiology of SCZ. Larger samples are required to evaluate this conclusion definitively.