Abstract
Many candidate gene studies use ‘intermediate phenotypes’ instead of disease diagnoses. It has been proposed that intermediate phenotypes have simpler genetic architectures such that individual alleles account for a larger percentage of trait variance. This implies that smaller samples can be used to identify genetic associations. Pharmacogenomic drug challenge studies may be an especially promising class of intermediate phenotype. We previously conducted a series of 12 candidate gene analyses of acute subjective and physiological responses to amphetamine in 99–162 healthy human volunteers (ADORA2A, SLC6A3, BDNF, SLC6A4, CSNK1E, SLC6A2, DRD2, FAAH, COMT, OPRM1). Here, we report our attempt to replicate these findings in over 200 additional participants ascertained using identical methodology. We were unable to replicate any of our previous findings. These results raise critical issues related to non-replication of candidate gene studies, such as power, sample size, multiple testing within and between studies, publication bias and the expectation that true allelic effect sizes are similar to those reported in genome-wide association studies. Many of these factors may have contributed to our failure to replicate our previous findings. Our results should instill caution in those considering similarly designed studies.
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Acknowledgements
This work was supported by NIH Grants DA007255 (ABH), DA02812 (HdW), and DA021336 and DA024845 (AAP). We thank Barbara E Engelhardt for providing imputed SNP genotypes and Margaret C Wardle for organization and preprocessing of the phenotype data.
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HdW has received a research grant from Unilever for a project unrelated to this study. ABH and AAP declare no potential conflict of interest.
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Hart, A., de Wit, H. & Palmer, A. Candidate Gene Studies of a Promising Intermediate Phenotype: Failure to Replicate. Neuropsychopharmacol 38, 802–816 (2013). https://doi.org/10.1038/npp.2012.245
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DOI: https://doi.org/10.1038/npp.2012.245
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