0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
Letter to the Editor   |    
Meta-Analysis and Psychiatric Genetics
STEPHEN J. PITTELLI, M.D.
Am J Psychiatry 2002;159:496-496. doi:10.1176/appi.ajp.159.3.496

To the Editor: In the article by Stephen V. Faraone, Ph.D., et al. (1), I find the use of meta-analysis to substantiate their claim perplexing. Meta-analysis may be a useful tool when examining studies with reasonably similar results, but using meta-analysis "to reconcile conflicting findings" (p. 1052) is a dubious endeavor. A significant majority of the studies in their meta-analysis either do not substantiate or contradict the claim that the 7-repeat allele of the dopamine D4 receptor gene is seen in higher prevalence in individuals with attention deficit hyperactivity disorder (ADHD). I certainly agree that the authors’ conclusion is "counterintuitive" (p. 1055). Notwithstanding that, I have a few criticisms of the meta-analysis itself.

1. While the authors ruled out the possibility that the results of an initial study (2) were false positive, using that same study in the meta-analysis along with attempts to replicate it is "stacking the deck." The prevalence of refuted initial false positives from molecular genetics studies of mental illnesses approaches 100% (3). Thus, this initial study should not be included in the meta-analysis (even if it is the most strongly positive study).

2. Despite the impressive mathematical demonstration of nonbias, I suggest there are a few potential areas of bias. First, Dr. Faraone included one of his own studies in the meta-analysis. Second, I can hardly imagine more biased groups to cull data from than "colleagues presenting such data at national meetings" and "the molecular genetics e-mail network" (1, p. 1053). Also, the authors stated, "Unfortunately, neither type of study has consistently confirmed the putative association between ADHD and the DRD4 7-repeat allele" (p. 1052). Unfortunate for whom?

3. Even if "it is reasonable to attribute differences among studies to chance fluctuations" (p. 1055), this does not account for the possibility that the studies regarding the D4 receptor gene 7-repeat allele simply provided the most false positives in comparison with molecular genetic studies of ADHD as a whole. A controlled meta-analysis of all molecular genetic studies for ADHD would be interesting; a null hypothesis should first assume that no such genes exist and that all significant findings to date, both positive and negative, are the result of "chance fluctuations."

4. The argument that ADHD is "mediated by many genes acting in concert" (p. 1052) is rather circular in that it is based primarily on the complete failure of molecular genetic studies to find such genes and replicate those findings. Whether or not ADHD genes truly exist (individually or acting in concert) remains an unproven assumption.

To claim that there is a link between ADHD and the D4 receptor gene 7-repeat allele "or some nearby gene" (p. 1052), a consistent replicable protocol must first be developed. A "small" association noted in a meta-analysis of conflicting studies does not meet the burden of proof.

Faraone SV, Doyle AE, Mick E, Biederman J: Meta-analysis of the association between the 7-repeat allele of the dopamine D4 receptor gene and attention deficit hyperactivity disorder. Am J Psychiatry  2001; 158:1052-1057
[PubMed]
[CrossRef]
 
LaHoste GJ: Genetics of complex behavioral traits: obesity, dopamine, and mood. Mol Psychiatry  1996; 1:302
[PubMed]
 
Faraone SV, Tsuang MT, Tsuang DW: Genetics of Mental Disorders. New York, Guilford, 1999
 
+

References

Faraone SV, Doyle AE, Mick E, Biederman J: Meta-analysis of the association between the 7-repeat allele of the dopamine D4 receptor gene and attention deficit hyperactivity disorder. Am J Psychiatry  2001; 158:1052-1057
[PubMed]
[CrossRef]
 
LaHoste GJ: Genetics of complex behavioral traits: obesity, dopamine, and mood. Mol Psychiatry  1996; 1:302
[PubMed]
 
Faraone SV, Tsuang MT, Tsuang DW: Genetics of Mental Disorders. New York, Guilford, 1999
 
+
+

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Related Content
Books
The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition > Chapter 6.  >
The American Psychiatric Publishing Textbook of Geriatric Psychiatry, 4th Edition > Chapter 6.  >
Dulcan's Textbook of Child and Adolescent Psychiatry > Chapter 15.  >
Dulcan's Textbook of Child and Adolescent Psychiatry > Chapter 15.  >
Dulcan's Textbook of Child and Adolescent Psychiatry > Chapter 23.  >
Topic Collections
Psychiatric News
Read more at Psychiatric News >>
PubMed Articles
The antennal sensory array of the nocturnal bull ant Myrmecia pyriformis. Arthropod Struct Dev 2014;():.doi:10.1016/j.asd.2014.07.004.