Closely linked cis-acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes.

In its expanded form, the fragile X triplet repeat at Xq27.3 gives rise to the most common form of inherited mental retardation, fragile X syndrome. This high population frequency persists despite strong selective pressure against mutation-bearing chromosomes. Males carrying the full mutation rarely reproduce and females heterozygous for the premutation allele are at risk of premature ovarian failure. Our diagnostic facility and previous research have provided a large databank of X chromosomes that have been tested for the FRAXA allele. Using this resource, we have conducted a detailed genetic association study of the FRAXA region to determine any cis-acting factors that predispose to expansion of the CGG triplet repeat. We have genotyped SNP variants across a 650-kb tract centered on FRAXA in a sample of 877 expanded and normal X chromosomes. These chromosomes were selected to be representative of the haplotypic diversity encountered in our population. We found expansion status to be strongly associated with a approximately 50-kb region proximal to the fragile site. Subsequent detailed analyses of this region revealed no specific genetic determinants for the whole population. However, stratification of chromosomes by risk subgroups enabled us to identify a common SNP variant which cosegregates with the subset of D group haplotypes at highest risk of expansion (chi(1)(2)=17.84, p=0.00002). We have verified that this SNP acts as a marker of repeat expansion in three independent samples.

Haplotypic determinants of instability in the FRAX region: Concatenated mutation or founder effect?

The fragile X triplet repeat expansion at Xq27.3 has been shown to be associated with mutation or instability 600 kb distal at the FMR2 repeat locus. Concatenated mutation, whereby a mutation at one locus somehow interacts with mutation, recombination, deletion, or transposition at another locus, is a possible explanation. In this study we examine evidence from a sample of over 7,000 independent haplotypes from the FRAX region. We adopt the use of cladistic groups to more thoroughly define the properties of these haplotypes, and in doing so isolate one group of haplotypes which may be predisposed to the phenomenon of concatenated mutation. Distinguishing concatenated mutation from founder effects is difficult within a single population. We present our evidence for and against concatenated mutation, and in the process describe a previously undefined mutation at FRAXE.

Allelic association with SNPs: metrics, populations, and the linkage disequilibrium map.

Comparison of different metrics, using three large samples of haplotypes from different populations, demonstrates that rho is the most efficient measure of association between pairs of single nucleotide polymorphisms (SNPs). Pairwise data can be modeled, using composite likelihood, to describe the decline in linkage disequilibrium with distance (the Malecot model). The evidence from more isolated populations (Finland, Sardinia) suggests that linkage disequilibrium extends to 427-893 kb but, even in samples representative of large heterogeneous populations, such as CEPH, the extent is 385 kb or greater. This suggests that isolated populations are not essential for linkage disequilibrium mapping of common diseases with SNPs. The in parameter of the Malecot model (recombination and time), evaluated at each SNP, indicates regions of the genome with extensive and less extensive disequilibrium (low and high values of in respectively). When plotted against the physical map, the regions with extensive and less extensive linkage disequilibrium may correspond to recombination cold and hot spots. This is discussed in relation to the Xq25 cytogenetic band and the HFE gene region.

DNA forensic science 1995.

After digression by a National Research Council committee, forensic use of DNA identification is returning to methods that do not violate population genetics and statistics. Polemic has been replaced by normal science as advances are made in molecular techniques and presentation of evidence. Rigorous quality control over the chain of custody and likelihood calculations still need to be implemented, and evidence extended on the structure of forensic populations and the operating characteristics of alternative tests.

Reproductive and menstrual history of females with fragile X expansions.

FRAXA premutations have been associated with premature ovarian failure (POF) or menopause before the age of 40. We have studied women in families ascertained because of a mentally retarded full mutation relative and determined their age of menopause, serum hormone levels in premenopausal individuals and the outcome of any pregnancies. Survival analysis was used as a measure of menopause and demonstrated a significant decrease in age of menopause in premutation carriers compared with their full mutation carrier and normal relatives. Serum FSH was also raised in premutation carriers, although oestradiol, inhibin A and inhibin B were not significantly different. However, we did not find an excess of dizygous twins or pregnancy loss/trisomies, both of which are associated with aging ovaries. Thus premutation carriers as a group have an earlier menopause and raised serum FSH but do not appear to manifest other features of an aging ovary.

Combined segregation and linkage analysis of inflammatory bowel disease in the IBD1 region using severity to characterise Crohn's disease and ulcerative colitis. On behalf of the GISC.

Inflammatory bowel disease (IBD) is a chronic relapsing disorder affecting the gastro-intestinal tract and is subdivided into two main subtypes: Crohn's disease (CD) and ulcerative colitis (UC). Although the aetiology of IBD is unknown, a strong genetic susceptibility is suggested and different candidate regions have been identified for both CD and UC. The IBD1 region on chromosome 16 has been confirmed to be important for susceptibility to CD, whereas conflicting evidence has been obtained for UC. We performed a combined linkage and segregation analysis in the identified IBD1 region on a sample of 82 extended families with IBD using a parametric method implemented in the computer program COMDS. This approach allows simultaneous evaluation of linkage while estimating the mode of inheritance and to include severity of the trait to characterise the CD and UC phenotypes. Our results are consistent with the presence of a major gene in the IBD1 region close to D16S408 involved in both UC and CD. Furthermore, our data support evidence that a single mutation in the gene leads more frequently to UC, whereas inheritance of two mutant alleles results in the more severe CD. In our study the IBD1 locus was found to have a major role in IBD predisposition in the Italian population.

Stability and haplotype analysis of the FRAXE region.

FRAXE full mutations are rare and appear to be associated with mild mental retardation. As part of a screening survey of boys with learning difficulties to determine the frequency of full and premutations, we have collected data on the frequency of instability at FRAXE for about 4000 transmissions and the haplotype for over 7000 chromosomes. The distribution of FRAXE repeats was similar to other English populations but differed from two North American Caucasian series. Observed instability at FRAXE was rare but increased with increasing repeat number, and there were no expansions into the full mutation range, except in pedigrees ascertained through a full mutation. Haplotype analysis suggested division into five groups with each group having a characteristic distribution of FRAXE repeats. Fourteen of the 15 full mutations occurred on a single haplotype and this haplotype also had a significant excess of intermediate-sized alleles, suggesting that full mutations originate from large normal alleles. However, a related haplotype also had a significant excess of intermediates but we observed no full mutations on this haplotype, suggesting either loss or gain of stability determinants on it. We suggest that whilst triplet repeat size is a significant predisposing factor for expansion at FRAXE other genetic determinants are also likely to be important.

Genetics of hyperuricemia in families with gout.

Complex segregation analysis supports the polygenic hypothesis of Hauge and Harvald and Neel et al, according to which hyperuricemia ascertained through gout is rarely due to a major gene, evidence for which is not significant in two studies that were considered to favor a major locus.

Erythrocyte catechol-O-methyltransferase activity: genetic analysis in nuclear families with one child affected by Down syndrome.

Erythrocyte catechol-O-methyltransferase (COMT) activity was measured in 142 members of 32 nuclear families in which one child had Down syndrome (DS). The mean activity in subjects with trisomy 21 appears higher than in parents and sibs, though not significantly so. However, this fact does not seem to modify the properties expected for a trait genetically controlled in a diploid population. The commingling analysis of the COMT activity in the whole group, and in each subgroup of relatives, suggests a mixture of two or, more likely, three components, the latter being in agreement with a transmission model of genes without dominance. The most parsimonious hypothesis supported by the mixed model segregation analysis is that of an additive major locus (d = 0.5) with an estimated frequency of 0.40 +/- 0.03 for the COMTH gene, to which a small polygenic effect (H = 0.067) can be added. This hypothesis is supported further by the analysis of family resemblance, r = 0.45 +/- 0.12 being the maximum likelihood estimator of the intraclass correlation among sibs. The higher COMT activity in DS subjects may reflect a situation of general enzyme disorder only indirectly connected with trisomy of chromosome 21.

Genetic and environmental determinants of periodontal disease.

Reanalysis of data on periodontal disease in 241 families [Chung et al, 1977b], based on an extended and more satisfactory path model [Rao et al, 1979], failed to detect significant heritability, and concluded in favor of cultural inheritance only, without maternal effects or intergenerational differences. The most parsimonious hypothesis yields a relative variance component of 0.338 +/- 0.024 due to indexed environment for both children and adults, the remainder (1.0--0.338 = 0.662) being due to residual nongenetic factors.

Complex segregation analysis and computer-assisted genetic risk assessment for Duchenne muscular dystrophy.

Two hundred forty-four Toronto pedigrees of Duchenne muscular dystrophy patients have been partitioned into nuclear families with pointers for complex segregation analysis under a mixed model. The model takes into account the major X-linked locus and a multifactorial transmissible component for creatine kinase activity in females. The incidence in the province of Ontario is estimated to be 292 per million male births. The proportion of sporadic cases is 1/3, demonstrating equal mutation rates in males and females. A multifactorial component (H = 0.379) contributes to family resemblance for creatine kinase measurements. Examples are presented of the application of a computer program, COUNSEL, to derive genetic risks for genetic counseling with consideration of the multifactorial component.

Linkage studies in spinocerebellar ataxia (SCA).

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.

Chromosome anomalies as predictors of recurrence risk for spontaneous abortion.

Reproductive histories and chromosomes of spontaneous abortions were studied by segregation analysis in 1890 sibships ascertained through a cytogenetically studied abortion. Normal karyotypes are associated with recurrent abortion. Among abnormal karyotypes, trisomy has an elevated recurrence risk even after adjustment through a liability indicator for maternal age. Possible mechanisms and conflicting evidence in the literature on trisomy are discussed. None of these differences in recurrence risk is large enough to play a significant numerical role in genetic counseling.

Oculoauriculovertebral anomaly: segregation analysis.

Seventy-four families of probands with oculoauriculovertebral anomaly were evaluated, including 116 parents and 195 offspring. Relatives were examined to identify ear malformations, mandibular anomalies, and other craniofacial abnormalities. For segregation analysis using POINTER, selection of the sample was consistent with single ascertainment. Different population liabilities were used for probands and relatives, because affection was narrowly defined for probands and broadly defined for relatives. The hypothesis of no genetic transmission was rejected. The evidence favored autosomal dominant inheritance; recessive and polygenic models were not distinguishable.

Segregation analysis of complex phenotypes: an application to schizophrenia and auditory P300 latency.

Traditional models of the genetic transmission of human diseases have often assumed that the phenotype is a simple dichotomous trait, which is unrealistic for many psychiatric conditions, and may result in loss of valuable information. We describe a new model for complex phenotypes, implemented in the program COMDS, which subclassifies normal and affected individuals into polychotomies correlated with the underlying genetic liability to the disorder. The model is applied to 18 Scottish pedigrees ascertained for schizophrenia, in which auditory P300 latency had been measured as a possible correlate of the genetic predisposition to schizophrenia. The results suggest that there may be a major locus for schizophrenia, but that there are also other familial determinants, possibly a second modifier locus. In addition, the results indicate that auditory P300 latency may be a useful measure of the genetic predisposition to schizophrenia among asymptomatic relatives, although the relationship between P300 latency and the degree of genetic predisposition in clinical cases was not significant, presumably because other factors are operating on P300 latency. Because of the possible selection biases in this sample, there is a need to replicate these findings in systematically ascertained pedigrees.

Darkness in El Dorado: human genetics on trial.

A recent book by a freelance journalist makes major accusations against genetic studies by J. V. Neel in the Amazon a generation ago. Contrary to these charges, there was no connection of Neel's work with human experiments conducted by the Rochester Manhattan project twenty years earlier, nor did the studies serve as a control for survivors of the atomic bombs in Japan. Neel was not a eugenicist. His program of measles vaccination reduced mortality, and was not in any sense an experiment. Given the passage of time and lack of supporting evidence, further investigation of these charges is pointless. However, the political climate in which human populations are studied has changed dramatically over the last generation. Unless guidelines reflect an international consensus, the benefits of population studies to human welfare and science will be jeopardized. The World Health Organization guidelines should be extended to cover current research.

[Genetic factors involved in asthma and atopy. Studies in British families]. / Facteurs génétiques impliqués dans l'asthme et l'atopie. Etudes dans les familles britanniques.

Both asthma and atopy run families indicating a strong genetic component. To investigate possible candidate gene regions, we have recruited 131 families without reference to atopy and asthma (random sample) and 60 extended families with two or more members affected by asthma (multiplex sample). Using both candidate and genome screen approaches, we have been able to provide evidence supporting the presence of candidate genes on chromosome 11q (E237G) and 12q but we have been unable to confirm reports of linkage and association for asthma on 5q. Our experience to date suggests that larger numbers of families are needed to increase the confidence of gene localisation and there is a need to improve the phenotypic description of asthma. Finally, it is essential that claims for linkage or association are confirmed in different populations using the same markers.