Haseman & Elston (1972) introduced a sib pair method using classical regression analysis to detect linkage between a polymorphic marker locus and any quantitative trait locus. Most of the diseases mapped to date follow simple Mendelian, single locus transmission. But there are many familial diseases that do not follow simple Mendelian segregation, for example diabetes, several forms of cancer, etc. In this paper, we extend Haseman and Elston's sib pair method to two unlinked quantitative trait loci each linked to one of two unlinked polymorphic marker loci. For the two-locus epistatic model, we give a general formulation of the complete regression model and details of the regression coefficients in terms of variance components.

Three apolipoprotein B (apoB) genetic polymorphisms, the XbaI, MspI and EcoRI restriction fragment length polymorphisms (RFLPs), were analysed for 221 individuals in Senegal by polymerase chain reaction. Allelic frequency determination revealed that this population has 0.79 XbaI− (X−), 0.96 MspI+ (M+), and 0.89 EcoRI+ (E+). Major genotypes were X−/X− (0.62), M+/M+ (0.92) and E+/E+ (0.80). The XbaI allele frequency is different (p<10−9) from that in Caucasians (0.47) and from that in Mongoloids (0.98). Significant differences between Senegalese and Caucasians, and between Senegalese and Mongoloids were also observed for the EcoRI and MspI alleles of the apoB genes.

The Haseman & Elston (1972) sibling-pair regression method has been used to detect and estimate the variance contribution to observed values of a quantitative trait by allelic variation in specific candidate genes. The procedure was developed under a model with a single biallelic trait locus. This assumption does not hold for several known systems. In this paper we prove that for candidate gene analysis the Haseman–Elston procedure extends to the case of multiple trait loci, each possibly having more than two alleles. Simulation experiments comparing single-locus to two-locus models show that fitting the extended regression equations maintains nominal significance levels, but the power to detect linkage to trait variation is not improved by including additional loci. These results indicate that the original proposal is statistically robust to violations of the underlying genetic model. Practical issues associated with quantifying the relative variance contribution by individual loci are also discussed. Applications of the extended regression equations to lipoprotein(a) and high density lipoprotein cholesterol are given for illustration.

A score statistic for testing the Hardy–Weinberg law for data sampled from several populations with different allele frequencies is derived assuming a common coefficient of disequilibrium (odds ratio-type) across strata. The assumption can be examined by a chi-square goodness-of-fit test. It is unlikely such a model would be rejected in typical studies involving human populations. Under this model, a Wald-type test has substantially less power than the score test. An approximate formula for the sample size required for a specific power of the stratified score test for detecting departure from equilibrium is given.

The robust sib-pair method introduced by Haseman & Elston (1972) is one of the most widely circulated allele-sharing methods for linkage analysis. The procedure evaluates linkage by significance testing of a regression coefficient and, hence, a standard t-test has traditionally been applied despite known violations of the statistical assumptions underlying the test. We present a permutation based reference distribution for the estimate of the regression coefficient that is motivated by genetic principles rather than by standard regression testing procedures. The permutation test approximates Mendelian co-segregation under the null hypothesis of no linkage, making it a very natural approach. Theory and simulations show that the conventional t-test approximates the permutation test quite well, even when dependent sib pairs are used for analysis. These results thus indirectly address concerns over the t-test. To illustrate the permutation test using real data we applied the procedure to two lipoprotein systems that have been well characterized.

Organized by the Institute of Medical Statistics and Epidemiology, Technische Universität München, Klinikum rechts der Isar and by the AG Population Genetics and Genome Analysis of the International Biometrics Society, German Region

We previously sequenced the 4333-nucleotide cDNA of the COPA (HEP-COP) gene which encodes the human homologue of the α-subunit of the coatomer protein complex, involved in intracellular protein transport. Within the 3′ untranslated region at nucleotides 4049–4333 was observed an Alu repeat containing conserved A and B block elements, and showing high homology to the human Alu-Sx subfamily consensus sequence. Upstream of the Alu repeat were noted a TATA box, a CAAT motif and two activating transcription factor (ATF)-like binding sites, which represent putative regulatory elements directing Alu transcription. In addition, the 25 and 35 N-terminal amino acid residues of COPA and its bovine homologue were identical to xenin-25 and proxenin, respectively. Xenin-25 is a gastrointestinal hormone that stimulates exocrine pancreatic secretion. This peptide is related to xenopsin, neurotensin and neuromedin N which are bioactive peptides derived from larger precursors via proteolytic cleavage by cathepsin E at processing sites determined by conserved C-terminal sequences, i.e. proline/valine-X-X-hydrophobic amino acid. Given the conformity of the C-terminal residues of xenin-25 (PWIL) and of its progenitor molecule, proxenin (VIQL), it is proposed that these peptides are generated by a similar mechanism of post-translational modification involving a parent precursor represented by the α-subunit of coatomer.

The chromosomal location of the human fast skeletal muscle troponin C (TNNC2) gene was determined using somatic cell hybrids. PCR-based analysis of a ‘monochromosomal’ hybrid panel identified the presence of the TNNC2 gene on human chromosome 20 and subsequent analysis of the Genebridge4 radiation hybrid panel located the gene between D20S721 and GCT10F11 with a lod score of >3.

We have determined the chromosomal location of the human cardiac/slow skeleletal muscle troponin C gene (TNNC1) to the short arm of chromosome 3 using somatic cell hybrids. PCR-based analysis of a ‘monochromosomal’ hybrid panel identified the presence of the TNNC1 gene on human chromosome 3 and subsequent analysis of the Genebridge4 radiation hybrid panel located the gene between D3S3118 (7·3cR) and GCT4B10 (4·2cR) with a lod score of >3·0.

A new CYP17 gene abnormality was found in three Japanese patients with 17α-hydroxylase deficiency (17OHD). These patients were children from consanguineous marriages, but from two apparently unrelated families: one patient with 46, XY karyotype, and two siblings with 46, XX and 46, XY karyotypes. They were all raised as girls and presented with amenorrhea, eunuchoid appearance and hypertension. Gene analysis revealed two base-pair (TG) deletion in exon 5 (codons 300, 301) of the CYP17 gene. This deletion could be expected to alter the reading frame resulting in the lack of a haem-binding region (Cys 442) due to a premature stop codon at position 333. This small mutation may account for the patients' clinical manifestations of 17OHD.

Ann. Hum. Genet. (1997), 61, 15–24

In this paper we described the physical map of a 1·9 Mb region in chromosome region 13q12. Although in the text we described that the motivation for this effort was to identify the breakpoint in an 8;13 translocation associated with myeloproliferative disease, none of the results presented in fact referred to that localization. However, a reference to the position of a breakpoint was given in Figure 2 and was derived from a figure constructed from early mapping data and submitted by mistake instead of the corrected figure which should not have included this information. We now know that this is not the position of the translocation breakpoint. All of the other mapping details in Figure 2 are correct. The authors regret this error and any inconvenience it may have caused.

Sponsored by the Oasi Institute for Research on Mental Retardation and Brain Aging Genetics is a rapidly growing field of medical science, which reveals molecular mechanisms of biological phenomena in health and disease. For this reason, we selected the topic ‘Neurogenetic Disease: From Molecule to Patient’, for the 4th International Symposium on Brain Dysfunction to be held September 1997. Various aspects of neurogenetic diseases: phenotype, pathology, pharmacology, biochemistry, genetics, animal models, and treatment will be discussed. We hope that this international meeting will further promote research in this field in order to understand pathogenesis as well as to develop new therapeutic approaches to genetic diseases affecting the nervous system.