To determine whether HLA-linked genes on chromosome 6 influence susceptibility to depressive disorders, we tested hypotheses concerning the distribution of HLA haplotypes among specific constellations of affected and unaffected family members. HLA haplotype identity among pairs of affected siblings in families with two affected siblings and among pairs of older unaffected siblings in families with one or two affected siblings was increased over random expectation (P less than 0.005). There was no increase in HLA haplotype identity among affected siblings in sibships with more than two affected members. When parents had a relative difference in estimated load of genes for susceptibility, HLA haplotypes were randomly transmitted to unaffected or affected children from the affected, "high-load" parent, but not from the unaffected, "low-load" parent (P less than 0.001). These results locate a gene contributing to susceptibility to depressive illness on chromosome 6 and provide a second example of the value of the hypotheses in defining the genetic bases of nonmendelian, familial diseases.
A locus, LP, that determines quantitative variation of Lp(a) lipoprotein phenotypes is linked to the plasminogen (PLG) locus (peak lod score = 12.73). This linkage relationship assigns a locus with alleles that have an affect on risk for coronary artery disease to the long arm of chromosome 6.
HLA typing was conducted on 577 family members of 86 families having at least two first-degree family members with a lifetime history of major depression or bipolar disorder. The results were combined with a follow-up study of 10 Newfoundland kindreds and with the data obtained from our previous studies, giving a total cohort of 117 families of diverse ethnic and geographic origin. There was increased sharing of HLA haplotypes, as compared with random expectation, over all possible pairwise comparisons both in the follow-up studies (P less than 0.025) and in the total data (P less than 0.01). The increase in HLA haplotype sharing over random expectation was greater if comparisons within heavily loaded sibships (by prior convention, sibships with three or more affected siblings) were omitted from the analysis (P less than 0.002). There was also non-random transmission of HLA haplotypes in 50 families selected for a low-load, unaffected parent (P less than 0.005). Thus, we conclude that genes in the HLA region of chromosome 6 constitute one of the elements in the multifactorial etiology of affective disorder. This conclusion does not depend on any assumption concerning genetic heterogeneity or epistasis or on specific modes of transmission, penetrance values or linkage distances. In addition, the data suggest that chromosome 6 region genes may have a different effect in unipolar and bipolar illness.
Two new alleles (A1B*3 and A1B*4) of human plasma (α1B -glycoprotein (α1B) were reported. α1B phenotyping was done by using either a simple method of two-dimensional (2-D) agarose gel-horizontal polyacrylamide gel electrophoresis (PAGE) followed by protein staining or by one-dimensional horizontal PAGE and immunoblotting. Seven different α1B phenotypes (1–1, 1–2, 1–3, 1–4, 2–2, 2–3 and 3–3) were observed; phenotypes 1–3 and 1–4 were differentiated from each other only by the 2-D method. The respective frequencies of A1B*1, A1B*2, A1B*3 and A1B*4 alleles in the studied populations were estimated as follows: American Blacks (New York) 0.732, 0.204, 0.064, 0; American Whites (New York) 0.947, 0.053; Czechs (Mělník) 0.964, 0.034, 0, 0.002; Slovaks (Bratislava and Trenčin) 0.977, 0.023, 0, 0. The population of American Blacks showed a much higher degree of α1B polymorphism (polymorphism information content = 0.37) than the Caucasian populations that have been studied.
Pericentric inversion has been suggested as one possible explanation for an abnormally located, human somatic cell autosomal centromere in twenty-one instances (reviewed in Jacobs
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