Gm, Km, and HLA in insulin-dependent type I diabetes mellitus. A log-linear analysis of association.

Two hundred sixty families, in which at least one family member had insulin-dependent (type I) diabetes mellitus (IDDM), were typed for HLA antigens and the Gm and Km allotypes. Frequencies of Gm and Km allotypes in the diabetic subjects were compared with family controls (oldest nondiabetic sibling within a family). There were no significant differences between patients and controls for either Gm or Km allotype frequencies considered individually. When the log-linear model was used to analyze subjects and sibling controls, three significant findings emerged. First, there was a significant HLA-Gm interaction, indicating nonrandom segregation of HLA antigens with Gm allotypes, regardless of disease status. Second, there was, as expected, a significant HLA-IDDM interaction, indicating that HLA type is nonrandom with respect to IDDM status. Third, there was a significant HLA-sex-Gm-IDDM interaction, indicating that combinations of HLA antigens, Gm allotypes, and sex may play an important role in defining risk for IDDM. Thus, Gm and sex interacting with HLA may reflect the influence of an unlinked modifier previously hypothesized for IDDM pathogenesis.

Evolutionary conservation of equine gc alleles and of Mammalian gc/albumin linkage.

Ancient origin of the equine vitamin D binding protein (Gc) polymorphism is suggested by the finding of two alleles, Gc(F) and Gc(S), in each of three equine subgenera, Equus, Asinus and Hippotigris. The equine Gc and albumin loci are closely linked (lod score = 6). Although no recombinants were observed, the data are not inconsistent with a map distance similar to the 2 centimorgans reported for the human albumin/Gc linkage relationship. Gametic association between the Gc(F) and Alb(F) alleles appears probable in the American Standardbred horse, perhaps as a result of population structure. Since Gc and albumin are both polymorphic in rodents and possibly other orders, this linkage group will be useful for studies of the evolution of mammalian linkage groups, as well as for a comparison of meiotic recombination frequencies and linkage disequilibria in different species.

Genetic marker studies in a family with unipolar depression.

A study of genetic markers was undertaken in a kindred containing 19 individuals affected with a depressive illness. The pedigree was selected for study because the distribution of affected family members is consistent with transmission of an autosomal gene for susceptibility to psychiatric abnormality. Evidence against linkage of the postulated dominantly transmitted susceptibility gene with 29 segregating marker loci, including HLA, excluded the postulated gene from 6% of the autosomal genome. However, the distribution of HLA haplotypes in affected sibling pairs and within the family as a whole is compatible with the hypothesis that expression of affective disorder in this family depends in part on an HLA-linked susceptibility gene.

A robust test for assortative mating.

Testing for random mating in human populations is difficult due to confounding factors such as ethnic preference and population stratification. With HLA, the high level of polymorphism is an additional problem since it is rare for couples to share the same haplotype. Focus on an ethnically homogeneous population, where levels of polymorphism at HLA loci are more limited, may provide the best situation in which to detect non-random mating. However, such populations are often genetic isolates where there may be inbreeding to an extent that is difficult to quantify and account for. We have developed a test for random mating at a multiallelic locus that is robust to stratification and inbreeding. This test relies on the availability of genotypic information from the parents of both spouses. The focus of the test is on families where there is allele sharing between the parents of both spouses, so that potential spouses could share an allele. Denoting the shared allele at the locus of interest by A, then under the assumption of random mating, heterozygous parents AX should transmit allele A equally as frequently as allele X to their offspring. When there is positive (negative) assortative mating, A will be transmitted more (less) often than X. The power of the test has been computed in a number of situations. Data on high resolution HLA haplotypes from the Hutterite population were reinvestigated by the proposed test. The test detects significant negative assortative mating when the parental origin of the shared haplotype is taken into account.

Association between bipolar affective disorder and multiple sclerosis.

Ten patients from Monroe County, N.Y., had both multiple sclerosis and bipolar affective disorder. Epidemiologic data indicate that the expected number would be 5.4. This difference may indicate an association between these disorders.

Multiple sclerosis susceptibility. Interaction between sex and HLA.

The sex of patients with multiple sclerosis (MS) in relation to the sex, number, and relationship of affected relatives indicates an interaction between sex and autosomal genes in determining susceptibility to MS in some persons. This conclusion is confirmed by the observation that the proportion of laterally-related affected female pairs (siblings or cousins) who share the maximum possible number of HLA haplotypes is greater than that proportion in corresponding unlike-sex pairs.

Multiple sclerosis and affective disorder. Family history, sex, and HLA-DR antigens.

To investigate a possible genetic cause underlying the clinical association between multiple sclerosis (MS) and affective disorder, we studied 56 patients with MS for psychiatric and genetic (family history, sex, and HLA-DR) characteristics. The 2:1 ratio of females to males expected for patients with MS was observed in this sample (40:16), but the excess of females occurred entirely among the 31 MS patients with major affective disorder (27 females and four males). Bipolar probands with MS had significantly more relatives with affective disorder or MS than did unipolar probands with MS. The HLA-DR antigen frequencies in patients with MS categorized by type and family history of affective disorder suggest that it may be possible to validate such clustering of patients. We concluded that sex and other genetic factors are related to the affective symptoms in MS and emphasize the importance of psychiatric evaluation of these patients.

A genetic marker and family history study of the upstate New York multiple sclerosis cluster.

We report nine additional cases of new-onset multiple sclerosis (MS) among employees of an upstate New York manufacturing plant that uses zinc as a primary metal. These cases, identified during the decade 1980 to 1989, had clinical onset of the disease between 1979 and 1987. The new cases confirm the increased incidence of MS previously reported in the plant population for the 1970 to 1979 decade. The MS subjects in this occupationally based cluster do not seem different from other MS patients with regard to rates of familial MS or the frequencies of alleles for human leukocyte (HLA-DR) antigens or transferrin. The frequency distribution of alleles for transferrin (an iron- and zinc-binding protein) may differ in these and other MS subjects compared with controls.

Spinocerebellar ataxia in a large kindred: age at onset, reproduction, and genetic linkage studies.

We studied a large kindred with autosomal dominant spinocerebellar ataxia (SCA) to assess reproductive performance, the impact of genetic counseling, and linkage relationships of the SCA locus. Reproduction was not lower in those with SCA than in unaffected sibs or first cousins. Genetic counseling reduced reproduction during the risk period for development of SCA. Given autosomal dominant transmission of a single gene, we found strong evidence that the locus for SCA in this kindred is linked to the HLA loci.

Lean body mass in twins.

A study of 49 pairs of monozygous (MZ) twins and 38 pairs of same-sexed dizygous (DZ) twins showed that lean body mass (LBM), as determined by potassium 40 counting, is under genetic influence. Intrapair variances for LBM are much smaller than those for body fat, which suggests that LBM has a higher degree of heritability. There is a correlation between the magnitude of intrapair LBM differences and intrapair weight differences for both sets of twins, showing that environment is also an important influence. The effect of weight variation on LBM variation is greater for thin people than for those with appreciable burdens of body fat, an observation previously made on individuals who undergo a nutrition-induced weight change.

Tourette syndrome and HLA.

Five kindreds with multiple individuals manifesting Tourette syndrome (TS) or related abnormal movements were evaluated for linkage between TS and HLA-A, B, C and DR antigens. Families were selected to have a constellation of affected individuals which gave the appearance of transmission of a major susceptibility gene. All kindreds had at least two clearly affected first or second degree relatives. Although developmental neurobehavioral disorders are candidates for showing a relationship to specific tissue antigens, we found no evidence for a close linkage between a gene locus determining susceptibility to TS and the HLA loci.

Familial Alzheimer's disease in two kindreds of the same geographic and ethnic origin. A clinical and genetic study.

Alzheimer's disease (AD) occurred in 37 individuals from two kindreds of Jewish ancestry with a mode of transmission suggesting an autosomal dominant genetic trait. Both kindreds originated from Byelorussia and spoke the Lithuanian dialect of Yiddish. In one of the two families one case of pathologically confirmed AD occurred with clinical and neuropathological signs of Parkinson's disease. In the other family one case of amyotrophic lateral sclerosis and one case of Down's syndrome occurred, both without clinical or pathological signs of AD. In the single kindred tested, a study of the chromosome 6 markers HLA, Bf and GLO failed to reveal a correlation between the transmission of AD and the segregation of these markers. The association of increased aneuploidy of peripheral blood chromosomes with AD was not confirmed in either of these families. Genetic differences between the familial and the sporadic form of AD are discussed.

Evidence for linkage between the loci for transferrin and ceruloplasmin in man.

Lod score analysis indicates probable linkage between the loci for transferrin and ceruloplasmin at a recombination frequency of approximately 10-15%. This human linkage relationship is homologous to one previously reported for cattle.

Concerning the linkage relationships of the Gc and MNSs loci.

Lod scores for the linkage relationships of the Gc and MNSs loci are presented for data from a number of published pedigrees and 103 new families. Linkage may be excluded at a recombination frequency of less than 25% in males and 30% in females.

Linkage of GLO with HLA and Bf. Effect of population and sex on recombination frequency.

Further data on the linkage relationships of red cell glyoxalase I(GLO) with HLA and Bf are reported. The most likely order of loci is GLO: Bf: HLA-B: HLA-A. No sex difference in the frequency of recombination between GLO and HLA was noted, but recombination was more frequent for both males and females in the American black population than in the white population.

HLA and disease: predictions for HLA haplotype sharing in families.

An analysis of published data on the segregation of HLA haplotypes in families with more than one individual affected with insulin-dependent diabetes mellitus or multiple sclerosis yields three conclusions: (1) In families with unaffected parents, affected sib pairs are much more often HLA haplotype identical in sibships with two affected sibs than in sibships with three or four affected sibs (P less than .01). (2) In families with unaffected parents and HLA half-identical affected sibs, well siblings more often receive the single haplotype not found in the affected sibs than is expected by chance (P less than .05). (3) In families with one affected parent, well siblings of affected individuals may share with the affected child a haplotype from the unaffected parent less than 50% of the time (P less than .10). These results are consistent with the premise that in some non-Mendelian, familial, HLA-associated disease more than one gene may contribute to susceptibility to the disorder.

Equine markers genes. Polymorphism for group-specific component (Gc).

Polymorphism of equine Gc protein was demonstrated by immunofixation electrophoresis with a goat anti-human Gc antibody. Three different phenotypes, F, FS and S, were found. Family data supported the genetic theory of two autosomal codominant alleles, GcF and GcS. Both alleles occurred in Standardbred, Thoroughbred and Arabian horses and in Shetland ponies. A frequency of 0.23 for GcS in the American Standardbred horse indicates the system should be useful for problems of identification and parentage.

Analysis of the Toronto-Rochester Depression Study follow-up data confirms an HLA-region gene contribution to susceptibility to affective disorder.

Analysis of HLA haplotype distributions in relation to major affective disorder in affected sibling pairs and affected aunt or uncle and niece or nephew pairs confirmed that HLA-region genes do contribute to susceptibility to affective disorder. The data indicated that this effect may be greater in unipolar than in bipolar disorder, and more apparent in families with few affected members than in heavily loaded families. Nonrandom assortment of HLA haplotypes to affected and unaffected offspring in "low load" families occurred principally for the haplotype transmitted from the side of the family without affective disorder. We conclude that HLA-region genes contribute to but are not the only factor in susceptibility to major depression.