Interestingly, here is a GWAS (genome wide association study) of antisocial disorder that primarily implicates a gene associated with the HLA complex on chromosome 6:
In the past, we have posited that antisocial disorder is a risk factor in non-sanguine A and PA types reared in an unfavorable environment.
The above study is interesting in that the study group likely contains a surfeit of non-sanguine types, which means that although fewer study group subjects have the N trait, by entanglement a greater number will have the A trait. (Finland is an ideal habitancy for such a study, since although presumably having a sizable prevalence of non-sanguine types, the control groups should be largely sanguine and non-aggressive).
Initially, we suspected that it was the "A locus" that was hiding on chromosome 6, but this study is equally consistent with the "N locus". So, the HLA region of chromosome 6 remains a site of interest regarding either the N or A loci.
* HLA ASSOCIATION WITH BEHAVIOR
To the Editor: More and more diseased states are being found to be associated with the histocompatibility (HLA) antigens, which are coded for by a group of genes located on the short arm of chromosome 6. These states include venerable systemic diseases such as juvenile-onset diabetes mellitus [1,2] and autoimmune thyroiditis , as well as disorders of behavior such as endogenous depression , schizophrenia [5,6], and perhaps even susceptibility to panic attacks . However, it is becoming increasingly evident that the genetic susceptibility to most of these states does not lie in particular antigens coded for by the HLA genes. Rather, the more likely hypothesis being advanced [1-4] is that these conditions are predisposed by genes that lie in the close vicinity of the HLA loci, in linkage disequilibrium with them.
The tentative conclusion that "genes" in the region of the HLA loci may predispose both to systemic disease and to abnormal behavioral states merits our greatest attention. In fact, many of the HLA-associated systemic diseases had, over the years, been noted to be associated with patterns of behavior –– even to the point of being classified by psychiatrists as "psychosomatic diseases." We need only mention juvenile-onset diabetes mellitus , Graves' disease , peptic ulcer , inflammatory bowel disease , rheumatoid arthritis [9,10], and systemic lupus erythematosus . For some of the conditions (e.g., ulcerative colitis, Graves' disease, rheumatoid arthritis) rather distinct personality patterns have been reported [9,10]. Finally, with regard to rheumatoid arthritis, the striking finding has emerged that the conditions of rheumatoid arthritis and schizophrenia tend to be mutually exclusive [12,13].
What are we to make of these findings? If we keep in mind Occam's Razor –– that the explanation most likely to be correct is the one that explains the greatest number of observations with the fewest suppositions –– then we are led to the following hypothesis: there exists a major polymorphic gene on chromosome 6 in the neighborhood of the HLA loci that can simultaneously confer susceptibility to systemic disease and behavior disorder. The precise nature of the phenotypic expression of such a pleiotropic gene would be dependent on other genes and on environmental factors. Variable expression of such a single gene could explain: 1) the overlap in the clinical presentations of some of the HLA-associated diseases, 2) the association of a given systemic disease with certain "personality traits," and 3) the mutual exclusiveness between a given systemic disease and a certain abnormal mental condition. Finally, it is possible that the presumed gene in question could be a determinant of recognizable personality traits in the absence of overt systemic disease, i.e., at the limit of incomplete penetrance.
In short, we speculate that various investigators in somewhat different fields are all pointing to the same gene on chromosome 6. No doubt some readers will dismiss this as too simple an explanation. Nevertheless, it may be the correct one.
1. Neel J.V. (1977): loc. cit.
2. Cahill G.F., Jr. and McDevitt H.O. (1981): loc. cit.
3. Strakosch C.R., Wenzel B.E., Row V.V. and Volpe R. (1982): Immunology of autoimmune thyroid diseases. New England J. Medicine 307 1499-1507.
4. Weitkamp L.R. et al. (1981): loc. cit.
5. Gattaz W.F., Beckmann H. (1980): HLA-antigens and schizophrenia. Lancet (I) 98-99.
6. Mendlewicz J. and Linkowski P. (1980): HLA-antigens and schizophrenia. Lancet (I) 765.
7. Surman O.S., Sheehan D.V., Fuller T.C. and Gallo J. (1983): Panic disorder in genotypic HLA identical sibling pairs. Am. J. Psychiatry 140 237-38.
8. Dunbar F. (1943): loc. cit.
9. Weiner H. (1977): loc. cit.
10. Moos R.H. (1964): loc. cit.
11. McClary A.R. et al. (1955): loc. cit.
12. Nissen H.A. and Spencer K.A. (1936): The psychogenesis problem (endocrinal and metabolic) in chronic arthritis. New England J. Medicine 214 576-81.
13. Gattaz W.F., Kasper S., Ewald R.W. and Beckmann H. (1980): loc. cit.
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