S. Lawrence

GENETIC-ANALYSIS OF ATOPY AND ASTHMA AS QUANTITATIVE TRAITS AND ORDERED POLYCHOTOMIES

Traits related to atopy and asthma were defined in a random cohort of 131 families with three or more children. Correlation analysis provides no evidence of imprinting, maternal effect, or a major role of environment shared by sibs. Commingling analysis favours more than one distribution, the upper one being common for asthma and very common for atopy. Segregation analysis of rank‐transformed variables provides only equivocal evidence of major genes against a polygenic background but suggests that such genes (if present) are individually common and not of large effect. Segregation analysis under a two‐locus model gives consistent results with minimal distributional assumptions. To enter combined segregation analysis we favour a restricted model in which the major locus is additive on the liability scale and the pseudopolygenic modifier locus accounts for at least half the genetic variance. Total IgE and bronchial reactivity are proposed for meta‐analysis of atopy and asthma respectively. Genetic analysis of complex inheritance is discussed and it is shown that allelic association with random loci is not a feasible approach.

Algorithms for a location database

The algorithms that drive the Idb location database are described. The program captures data on genetic and physical maps and combines information from different sources into a summary map. To assure portability it was developed in Fortran on a SUN SPARCStation under Unix. The algorithms, which combine rule‐based seriation with a minimum deviance bootstrap, allow investigators and chromosome committees to produce a composite location in Mb that integrates partial maps. The program and manual are now available from the authors.

Exclusion from proximal 11q of a common gene with megaphenic effect on atopy

We have typed three markers on proximal 11q in 131 random families with three or more children studied for atopy. A summary map that includes the FCER1B candidate was constructed. Using a 2‐locus disease model, we performed combined segregation and linkage analysis of three models, none of which suggested linkage. Nine marker loci on other chromosomes were also negative. In the regions swept by these 12 markers we cannot rule out a rare gene, perhaps of large effect, nor a common gene of small effect. However, a common gene of large effect is excluded. These results and alternative strategies are discussed in the perspective of inconsistent evidence for a major atopy gene.

An integrated map of chromosome 9

An integrated map of 211 loci on chromosome 9 is presented for which 198 loci have genetic locations. The results of the analysis indicate very strong interference for the chromosome and positional variations in recombination rates, most extreme in the male map where there is an excess of recombination near the p telomere and a marked suppression of recombination in a large region that includes the centromere.

Evolutionary dynamics of the FMR1 locus.

Rare haplotypes for close flanking markers are associated with increased allele size and frequency of the fragile X mutation. Exceptional founder haplotypes can be identified, but many haplotypes with rare alleles contribute to full mutations.

The AD1 locus in familial Alzheimer disease

The AD1 locus on chromosome 21 (MIM 104300) maps to the β‐amyloid precursor locus (APP) at approximately 27·7 Mb from pter (10·9 cM in males and 33·9 cM in females), flanked proximally by D21S8 and distally by D21S111, with D21S124 and D21S210 close but of uncertain order. AD1 accounts for 63±11 % of multiplex Alzheimer pedigrees for which lod scores have been reported. Since a much smaller proportion of pedigrees have mutations in the cDNA for β‐amyloid (APP exons 16 and 17), it is likely that the AD1 locus spans controlling elements near those exons. There is no evidence for a second locus on chromosome 21. The remaining pedigrees may include sporadic cases as well as mutations at an AD2 locus on another chromosome.