Molecular Psychiatry
Dear Prof Lucinio,
Faraone SV, Spencer TJ, Madras BK, Zhang-James Y and Biederman J. Functional effects of dopamine transporter gene genotypes on in vivo dopamine transporter functioning: a meta-analysis. Molecular Psychiatry (2013), 1–10
We read with interest the systematic review and meta-analysis by Faroane et al 1 of the association between the SLC6A3 3’UTR polymorphism and in vivo striatal dopamine transporter (DAT) binding measured using molecular imaging studies.
They found that the 9R allele of dopamine active transporter (DAT) gene (SLC6A3) was associated with increased DAT activity in human adults. This conclusion was based on the single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies. However, we have a methodological concern that has a major implication for some of their findings. The findings from the PET imaging were based on two studies that used two different ligands 1(Figure 2). The analysis, as illustrated in the funnel plot 1 (Figure 2), shows that the standardised mean differences (SMD) from different striatal sub-regions within the same study were treated as independent measures. Clearly the DAT genotype is the same for a given subject irrespective of the region, and as such these are not independent measures. Furthermore, molecular imaging measures of dopamine in striatal sub-regions are highly correlated 2 and not independent due to partial volume effects 3,4. For these two reasons the analysis appears to have violated the requirement in a meta-analysis for measures to be independent 5. Additionally, while it is possible to combine the effect sizes from meta-analysis with two or more studies, at least N=6 has been suggested as a minimum below which findings are likely to be unreliable 6. In meta-analysis of n=2 studies, heterogeneity analyses are likely to underestimate the variance among studies 7. Finally, the inconsistencies between results of imaging studies may also be due to biological differences in the DAT protein expression as amine transporters are post-transcriptionally regulated by various kinases and phosphatases 8,9. For these reasons we are concerned that the conclusions may not be justified 1 and welcome clarification.
Footnotes
Disclosures:
Sudhakar Selvaraj, Federico Turkheimer and Oliver Howes report no competing interests.
Reference List
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