title: I just ran a thousand analyses: benefits of multiple testing in understanding equivocal evidence on gene-environment interactions.
abstract: BACKGROUND
  In psychiatric genetics research, the volume of ambivalent findings on gene-environment interactions (G x E) is growing at an accelerating pace. In response to the surging suspicions of systematic distortion, we challenge the notion of chance capitalization as a possible contributor. Beyond qualifying multiple testing as a mere methodological issue that, if uncorrected, leads to chance capitalization, we advance towards illustrating the potential benefits of multiple tests in understanding equivocal evidence in genetics literature.
  
  
  METHODS
  We focused on the interaction between the serotonin-transporter-linked promotor region (5-HTTLPR) and childhood adversities with regard to depression. After testing 2160 interactions with all relevant measures available within the Dutch population study of adolescents TRAILS, we calculated percentages of significant (p < .05) effects for several subsets of regressions. Using chance capitalization (i.e. overall significance rate of 5% alpha and randomly distributed findings) as a competing hypothesis, we expected more significant effects in the subsets of regressions involving: 1) interview-based instead of questionnaire-based measures; 2) abuse instead of milder childhood adversities; and 3) early instead of later adversities. Furthermore, we expected equal significance percentages across 4) male and female subsamples, and 5) various genotypic models of 5-HTTLPR.
  
  
  RESULTS
  We found differences in the percentages of significant interactions among the subsets of analyses, including those regarding sex-specific subsamples and genetic modeling, but often in unexpected directions. Overall, the percentage of significant interactions was 7.9% which is only slightly above the 5% that might be expected based on chance.
  
  
  CONCLUSIONS
  Taken together, multiple testing provides a novel approach to better understand equivocal evidence on G x E, showing that methodological differences across studies are a likely reason for heterogeneity in findings - but chance capitalization is at least equally plausible.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion regulation, Groningen, the Netherlands.
authors.forename: Vera E
authors.initials: VE
authors.lastname: Heininga
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion regulation, Groningen, the Netherlands.
authors.forename: Albertine J
authors.initials: AJ
authors.lastname: Oldehinkel
authors.affiliation: University of Groningen, Department of Sociology, Groningen, the Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Veenstra
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion regulation, Groningen, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Nederhof
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002649:Child Abuse; D003863:Depression / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008016:Life Change Events; D008297:Male; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D012737:Sex Factors; D055815:Young Adult
chemical_list: C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins