Methods are given for efficient calculation of the likelihood for multilocus linkage in families comprised of grandparents, parents, and children. Such families are being used in large-scale cooperative efforts to build a detailed linkage map of the human genome. The methods are illustrated by an application to loci on chromosome 13.
Data are now available on 9 pedigrees in detail and 4 pedigrees as lod scores only. Linkage to HLA is significant (Z = 5.53 at recombination rates of 0.223 in males and 0.327 in females). Tight linkage is excluded. Nine pedigrees which appear to be typical olivopontocerebellar atrophy (OPCA I) have recombination rates of 0.150 in males and 0.300 in females. The remaining 4 pedigrees are clinically atypical or include discrepant data and give no evidence for linkage. The symbol SCA1 is proposed for a locus on chromosome 6 (loosely linked to HLA), at which at least one allele produces OPCA I (Menzel type). It is not yet clear whether other clinical types are determined by alleles at different loci, although this is suggested by several pedigrees, including a Danish pedigree of OPCA with dementia. Linkage evidence will be decisive in delineating the ataxias.
Data from several different studies are reviewed suggesting that a subset of hypertension is associated with metabolic abnormalities involving lipids, insulin, and often obesity, all aggregating strongly in families. Persons with 'familial dyslipidaemic hypertension (FDH)' have an especially high risk of early coronary disease. The clinical and biochemical features of FDH are compared with Reaven's Syndrome X, familial combined hyperlipidaemia, dense LDL subfractions, diabetes, impaired glucose tolerance, central and general obesity, pre-diabetes, pre-hypertension, and heterozygous lipoprotein lipase deficiency. Some contribution from major gene effects is suggested in specific subsets reported in several different genetic studies reviewed in this report. It seems likely that multiple metabolic abnormalities are genetically heterogeneous. The data also suggest significant contributions from environmental factors such as diet and physical activity.
We have genetically mapped the genes encoding four human adrenergic receptors (ARs) of subtypes alpha 1C, alpha 2A, alpha 2B, and beta 1, which are prototypic G protein coupled receptors that mediate the physiological effects of neurotransmitters, hormones, and drugs. We placed these genes onto the Cooperative Human Linkage Center (CHLC) and Genethon framework maps, within confidence intervals with greater than 1000:1 odds. With multipoint analysis the alpha 1C gene (locus ADRA1C) mapped to the interval between NEFL and D8S283; alpha 2-C4, the gene encoding the alpha 2C AR (locus ADRA2C), mapped to the interval between D4S126 and D4S62; and the alpha 2-C10 (alpha 2A AR)/beta 1 haplotype (loci ADRA2A/ADRB1) mapped to the interval between D10S259 and D10S187. A fifth AR gene, beta 2, yielded significant LOD scores with markers on the long arm of chromosome 5; however, this locus (ADRB2) could not be mapped to any specific interval with odds of greater than 1000:1. The two AR genes that are completely linked, alpha 2-C10 and beta 1, were oriented on their shared 225-kb genomic fragment relative to the direction of transcription, with beta 1 being 5' to alpha 2-C10. The positioning of these genes on high-density framework maps allows them to be tested as candidates in a spectrum of diseases that might involve AR dysfunction.
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