Promise and pitfalls in the meta-analysis of genetic association studies: a response to Sen and Schinka

Munafò, Marcus R; Clark, Taane G.; Flint, Jonathan

doi:10.1038/sj.mp.4001706

Cited by 27 publications

(21 citation statements)

References 19 publications

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“…Had we chosen to report exclusively on the results of the 1991 survey, we would have drawn the conclusion that a significant association between 5-HTTLPR and anxiety-related traits is present, although the effect was in the other direction than expected. Therefore, not only different phenotypes should be measured, as suggested by Munafo et al (2005b), but they should also be measured repeatedly. This also provides the opportunity to analyse mean scores over occasions, which is more powerful because of the high number of subjects and the reduction of measurement error.…”

Section: Discussionmentioning

confidence: 99%

“…Even meta-analyses on the association between 5-HTTLPR and personality traits (Munafo et al 2003;Munafo et al 2005a;Schinka et al 2004;Sen et al 2004) or affective disorders (Lasky-Su et al 2005;Lotrich and Pollock 2004) reached conflicting conclusions. This might be partly due to methodological differences between the meta-analyses (Munafo et al 2005b;Schinka 2005;Sen et al 2005). Munafo et al (2005b), therefore, stated that ''Very large, well designed primary studies remain the most reliable way of obtaining reproducible results''.…”

Section: Introductionmentioning

confidence: 99%

“…This might be partly due to methodological differences between the meta-analyses (Munafo et al 2005b;Schinka 2005;Sen et al 2005). Munafo et al (2005b), therefore, stated that ''Very large, well designed primary studies remain the most reliable way of obtaining reproducible results''.…”

Section: Introductionmentioning

confidence: 99%

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Family Based Association Analyses between the Serotonin Transporter Gene Polymorphism (5-HTTLPR) and Neuroticism, Anxiety and Depression

et al. 2007

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We studied the association between the short/long promotor-based length polymorphism of the serotonin transporter gene (5-HTTLPR) and neuroticism, anxiety and depression. Subjects included twins, their siblings and parents from the Netherlands Twin Register (559 parents and 1,245 offspring). Subjects had participated between one and five times in a survey study measuring neuroticism, anxiety and depression. Offspring of these families were also approached to participate in a psychiatric interview diagnosing DSM-IV major depression. Within-family and total association between 5-HTTLPR and these traits were tested. Only three of the 36 tests showed a significant effect of 5-HTTLPR (P < 0.05). These effects were in opposite directions, i.e. both negative and positive regression coefficients were found for the s allele. No additive effect of the s allele was found for DSM-IV depression. Our results strongly suggest that there is no straightforward association between 5-HTTLPR and neuroticism, anxiety and depression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Family Based Association Analyses between the Serotonin Transporter Gene Polymorphism (5-HTTLPR) and Neuroticism, Anxiety and Depression

et al. 2007

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“…The reader is also referred to the interesting papers of Munafo et al 28,34,35 who examined the impact of publication bias (authors tend to publish only positive results -a tendency encouraged by most journals) and other methodological problems connected with meta-analysis. Munafo et al offered the sound advice that large studies, with sufficient power and employing multiple phenotype measures, is likely the best strategy towards resolving the role of DRD4 and 5-HTTLPR as well as other genes in partially determining the architecture of personality traits.…”

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confidence: 99%

The molecular genetic architecture of human personality: beyond self-report questionnaires

2006

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Molecular genetic studies of personality began with two high impact papers in 1996 that showed provisional associations between the dopamine DRD4 exon III repeat region and Novelty Seeking/Extraversion. These first two reports were shortly followed by an investigation linking Neuroticism/Harm Avoidance with the serotonin transporter (SLC6A4) promoter region polymorphism (5-HTTLPR). In the ensuing decade, thousands of subjects have been studied for association between these genes and personality, assessed by using self-report questionnaires, with erratic success in replication of the first findings for Novelty Seeking (DRD4) and Harm Avoidance (5-HTTLPR). Small effect sizes characteristic of non-Mendelian traits, polygenic patterns of inheritance and true heterogeneity between studies confound attempts to reach a consensus regarding the role of common polymorphisms in contributing to personality domains. Nevertheless, the current state of personality genetics is far from being bleak. Several new paradigms especially functional neuroimaging or 'imaging genomics' have strengthened the connection between 5-HTTLPR and anxiety-related personality traits. The demonstrations that early environmental information can considerably strengthen and even uncover associations between genes and behavior (Caspi's seminal studies and more recently the demonstration that early environment impacts on DRD4 and Novelty Seeking) are notable and herald a new era of personality genetics. Finally, consideration of the broader phenotypic expression of common polymorphisms (e.g. the 'social brain', altruism, etc.) and the use of new experimental paradigms including neurophysiological, neuropsychological and computer games that go beyond the narrow self-report questionnaire design will enable a deeper understanding of how common genetic polymorphisms modulate human behavior. Human personality, defined by Webster as the quality or state of being a person or the complex of characteristics that distinguishes an individual, surely requires a more encompassing view towards understanding its complex molecular genetic architecture.

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“…the majority of these studies were underpowered, with sample sizes being small relative to what is needed to draw conclusions based on the small effect size that can be attributed to a single gene. two studies that were adequately powered (Willis-Owen et al 2005;terracciano et al 2009) did not find a correlation, however, several meta-analyses did (Schinka et al 2004;Sen et al 2004;Munafo et al 2005). the latter two investigations clarified that finding a correlation was dependent upon the method of meta-analysis being used.…”

Section: Serotonin Transporter Imaging and Post-mortem Studies Of Suimentioning

confidence: 87%

Serotonergic modulation of suicidal behaviour: integrating preclinical data with clinical practice and psychotherapy

Boulougouris

Malogiannis

Lockwood³

et al. 2013

Exp Brain Res

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Promise and pitfalls in the meta-analysis of genetic association studies: a response to Sen and Schinka

Cited by 27 publications

References 19 publications

Family Based Association Analyses between the Serotonin Transporter Gene Polymorphism (5-HTTLPR) and Neuroticism, Anxiety and Depression

Family Based Association Analyses between the Serotonin Transporter Gene Polymorphism (5-HTTLPR) and Neuroticism, Anxiety and Depression

The molecular genetic architecture of human personality: beyond self-report questionnaires

Serotonergic modulation of suicidal behaviour: integrating preclinical data with clinical practice and psychotherapy

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