Monday, December 23, 2013

Dr. Kevin Beaver the Apostle

In the discussion following my previous video about monoamine oxidase A, I noted a new study with lead author Dr. Kevin Beaver. The study closely resembles his previous study of the 2-repeat allele, my analysis of which is well on its way to becoming my most popular blog essay. Once again, a small subset of African-American men from the National Longitudinal Study of Adolescent Health served as a comparison group for the eight African-American men, who possess this rare allele of the upstream promoter for MAOA and who had complete phenotype data. This time, the specific behaviors of shooting or stabbing replaced measures of psychopathic personality, arrests, and incarceration as the outcomes of interest. Despite the small sample size, the results were significant (odds ratio = 12.89, p < 0.05) because those with the allele had a fifty-percent chance of shooting or stabbing someone. For African-American men without this allele, the risk was only seven percent. Those with MAOA-2R were also more likely to have victimized multiple people based on their greater likelihood of admitting stabbing or shooting during multiple “waves” of study follow-up.

I still have concerns about population substructure. In a mixed population like African Americans, alleles associated with African ancestry like MAOA-2R might correlate with many other African alleles, and because MAOA-2R is so much more common in African Americans than whites and Asians, scientists have studied no other sample and no other race for behavioral phenotypes specifically for this allele. However, Guo et al previously demonstrated the functional differences between MAOA-2R and the other alleles in vitro.

This study bares the imprint of my influence. I previously sent Beaver a list of questions that reflected beliefs of mine about the research on this gene. Here was one such question:
In your studies of MAOA, you used the convention of including the 2-repeat and 3-repeat alleles in the category MAOA-L, but Guo et al “The integration of genetic propensities into social-control models of delinquency and violence among male youths” and Guo et al “The VNTR 2 repeat in MAOA and delinquent behavior in adolescence and young adulthood: associations and MAOA promoter activity” found that the 2-repeat allele had twice as much effect on violent delinquency as either the 3-repeat or 4-repeat alleles and that the 2-repeat allele had more effect than the dopamine genes DAT1 and DRD2. How do you justify following the MAOA-L convention rather than studying the 2-repeat allele separately?
In this study, Beaver et al make the following similar remark:
[A]lmost all of the prior research examining the effects of MAOA on antisocial behaviors has pooled the 2-repeat allele together with the 3-repeat allele. As the results of this study indicate, however, this approach may be misguided as the most powerful effects may be found within the 2-repeat allele and combining the 2-repeat allele with the 3-repeat allele may attenuate the main effects of MAOA.
I raised another concern in a separate question:
A disproportionate number of studies on MAOA and antisocial personality disorder were negative (Saito et al, Koller et al, Parsian et al, Lu et al, and Prichard et al). Why should antisocial personality disorder be a focus of genetic research? Should not the aggression or impulsive criteria of antisocial personality disorder be considered separately in genetic studies?
Beaver et al echo my concern:
Using an additive scale of antisocial behaviors may mask important heterogeneity that exists between the individual behaviors and MAOA genotype such that MAOA may be related to certain types of antisocial behaviors, but not others. As a result, to further unpack the nexus between MAOA genotype and serious violence, the current study examines only extreme violence as measured by shooting and stabbing behaviors.
Neuroskeptic, who has been a reader of the Unsilenced Science, responded to the study by saying, “Hmmm,” to which neurogeneticist Dr. Kevin Mitchell responded, “Grrrrr,” undoubtedly while pounding his chest. University of North Carolina geneticist Dr. Patrick Sullivan wrote, “I would have rejected wo review. Studies like these have not taught us much.” By “studies like these,” I assume he means the hundreds of corroborating studies pertaining to the MAOA gene, its enzyme, and its metabolites, but dismissive flippancy from genetics professors is the sign of the times. Mitchell passed along my recent video to his fellow GWAS Jihadists “based on the title,” which is clearly a Christmas miracle. I, for one, generally do not consider candidate-gene studies with large effect sizes to be evidence of no effect at all “by historical analogy.” In the past, interesting studies would lead to attempts to replicate the finding. Often some attempts would support, others would not, and a meta-analysis of all pertinent results would provide the final word. Now, some attempts support, and every attempt that does not support the original finding is evidence of a broader dysfunction in medicine or science, which are to blame for the media’s hype. Only a select few GWAS Jihadists have the moral courage to dismiss every positive finding with a self-righteous fist pound on the lectern. Nevertheless, Vimaleswaran et al determined that candidate-gene studies, which follow hypotheses about specific genes, show “evidence for enrichment” when compared to genome-wide association studies (for obesity) such that “the candidate gene approach retains some value.” Tielbeek et al attempted to test MAOA in a GWAS that only examined single nucleotide polymorphisms and found no effects for antisocial behavior. Of course, such a study could not directly examine the VNTR promoters that have drawn so much interest to this gene.

Eight is a small number of cases, but it is approximately the same as the number of cases of Brunner syndrome when that diagnosis was established in 1993, a diagnosis that only recently came into use for two additional families. When I first confronted the GWAS Jihadists, I asked them if their disbelief in the gene-environment interaction for MAOA-3R extended to a disbelief in Brunner syndrome. They defensively denied reaching that conclusion. The lesson is obvious: in order to establish the effect of MAOA-2R on violence as a trustworthy scientific finding, this allele’s effect must have an eponym. But which scientist should the disease immortalize? Will it be Guo syndrome or Beaver syndrome? (How about nooffensebut syndrome?) We could follow the example of entomologists, Quentin Wheeler and Kelly Miller, and name this after the greatest president of my lifetime: George W. Bush syndrome. However, as any graduate of medical school can attest, eponyms are evil. The study of genetics as it pertains to social sciences might gain the respectability of physics if it follows physics naming conventions. Just as flavors of quarks have creative names like strange and charm, the disease with symptoms of shooting people and stabbing people caused by the allele MAOA-2R should be called sunshine syndrome.

Beaver KM, Barnes JC, & Boutwell BB (2013). The 2-Repeat Allele of the MAOA Gene Confers an Increased Risk for Shooting and Stabbing Behaviors. The Psychiatric quarterly PMID: 24326626

Piton A, Redin C, & Mandel JL (2013). XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. American journal of human genetics, 93 (2), 368-83 PMID: 23871722

Tielbeek JJ, Medland SE, Benyamin B, Byrne EM, Heath AC, Madden PA, Martin NG, Wray NR, & Verweij KJ (2012). Unraveling the genetic etiology of adult antisocial behavior: a genome-wide association study. PloS one, 7 (10) PMID: 23077488

Vimaleswaran KS, Tachmazidou I, Zhao JH, Hirschhorn JN, Dudbridge F, & Loos RJ (2012). Candidate genes for obesity-susceptibility show enriched association within a large genome-wide association study for BMI. Human molecular genetics, 21 (20), 4537-42 PMID: 22791748

Sunday, December 8, 2013

The Stupid Stupidity Surrounding the Warrior Gene, MAOA, is Stupid

Byrd AL, & Manuck SB (2013). MAOA, Childhood Maltreatment, and Antisocial Behavior: Meta-analysis of a Gene-Environment Interaction. Biological psychiatry PMID: 23786983