bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping of human interferon regulatory factor 3 (IRF3) to chromosome 19q13.3–13.4 by an intragenic polymorphic marker
Authors: BELLINGHAM J. , GREGORY‐EVANS K. , GREGORY‐EVANS C. Y.
Published: March 2003

We have identified a highly polymorphic intragenic marker composed of two dinucleotide repeats in an intron of the human interferon regulatory factor (IRF3) gene. This polymorphic marker has allowed us to map IRF3 to the boundary of 19q13.3–13.4 between the polymorphic markers D19S604 and D19S206 close to KLK1. An intron is present in a homologous position in the mouse Irf3 gene, but lacks the dinucleotide repeats present in the human intron. Syntenic conservation between this region of 19q13.3–13.4 maps Irf3 to either mouse chromosome 7 or 17.
Increased parental age and number of pregnancies in Klippel–Trenaunay–Weber syndrome
Authors: LORDA‐SANCHEZ I. , PRIETO L. , RODRIGUEZ‐PINILLA E. , MARTINEZ‐FRÍAS M. L.
Published: March 2003

The Klippel–Trenaunay–Weber syndrome (KTWS) is generally thought to occur sporadically, following a somatic mutation model. However, in some cases, clinical manifestations of the syndrome have been found in family members, suggesting an autosomal dominant inheritance. Here we present an epidemiological analysis of a consecutive series of cases with KTWS identified in the Spanish Collaborative Study of Congenital Malformations (ECEMC). We found an increase in parental age and in the number of pregnancies, as well as familial occurrence of haemangiomas. These observations suggest a genetic contribution to the occurrence of KTWS.
Phylogeography of mitochondrial DNA in western Europe
Authors: RICHARDS M. B. , MACAULAY V. A. , BANDELT H.‐J. , SYKES B. C.
Published: March 2003

For most of the past century, prehistorians have had to rely on the fossil and archaeological records in order to reconstruct the past. In the last few decades, this evidence has been substantially supplemented from classical human genetics. More recently, phylogenetic analyses of DNA sequences that incorporate geographical information have provided a high‐resolution tool for the investigation of prehistoric demographic events, such as founder effects and population expansions. These events can be dated using a molecular clock when the mutation rate and founder haplotypes are known. We have previously applied such methods to sequence data from the mitochondrial DNA control region, to suggest that most extant mitochondrial sequences in western Europe have a local ancestry in the Early Upper Palaeolithic, with a smaller proportion arriving from the Near East in the Neolithic. Here, we describe a cladistic notation for mitochondrial variation and expand upon our earlier analysis to present a more detailed portrait of the European mitochondrial record.
Comprehensive mutational analysis of the TSC1 gene: observations on frequency of mutation, associated features, and nonpenetrance
Authors: KWIATKOWSKA J. , JOZWIAK S. , HALL F. , HENSKE E. P. , HAINES J. L. , McNAMARA P. , BRAISER J. , WIGOWSKA‐SOWINSKA J. , KASPRZYK‐OBARA J. , SHORT M. P. , KWIATKOWSKI D. J.
Published: March 2003

We performed a comprehensive analysis for mutations in the TSC1 gene using Southern blot analysis, and SSCP and heteroduplex analysis of amplified exons in 13 families with genetic linkage to the TSC1 region, 22 small families without linkage information, and 126 sporadic patients. 17 unique mutations were identified in 21 patients. Mutations were found in 7/13 (54%) TSC1‐linked families, 1/22 (5%) small families without linkage, and 13 of 126 (10%) sporadic cases. The mutations were all chain‐terminating, with 14 small deletions, 1 small insertion, and 6 nonsense mutations. In families with mutations, all individuals carrying a mutation met formal diagnostic criteria for TSC, apart from a 3‐year‐old girl who had inherited a deletion mutation, and who had no seizures, normal intelligence, normal abdominal ultrasound, and hypomelanotic macules only on physical exam. We assessed the incidence and severity of mental retardation in the 13 sporadic patients with TSC1 mutations versus the entire sporadic cohort, and found no significant difference. The observations indicate that TSC1 mutations are all inactivating, suggest that TSC1 disease occurs in only 15–20% of the sporadic TSC population, and demonstrate that presymptomatic TSC does occur.
Major gene control of human body height, weight and BMI in five ethnically different populations
Authors: GINSBURG E. , LIVSHITS G. , YAKOVENKO K. , KOBYLIANSKY E.
Published: March 2003

Pedigree samples were collected from five ethnically and geographically different populations: Kirghizians, Turkmenians, Chuvashians, Israelis and Mexicans. All studied individuals were assessed for body height, weight and BMI. The sample size in the studied pedigrees ranged from 381 to 1811 individuals. Segregation analysis of these traits preliminarily adjusted for sex and age was performed by means of program package man that provides parameter estimates for the major gene effects, for the residual within the genotype correlations between relatives and for the assortative mating. By the usual transmission probability tests, the ‘environmental’ model was strongly rejected for all measured traits in all 5 populations. The major gene mode of inheritance, however, was accepted for all traits. The results of analysis in 5 populations were remarkably similar, and showed that except for Mexican sample, the proportion of variance attributable to major gene effect ranged between 37 and 53% for body weight and height. In the Mexican sample it explained only about 14% of the body weight variation. The proportion of inter‐individual variation in BMI attributable to major gene effect was consistently lower in all populations in comparison with height and weight and ranged between 17 and 40%. Strong assortive mating in body height, as estimated by correlation between putative major gene genotypes in spouses, was found in four populations, not including Mexican pedigrees.
A branching non‐linear autoregressive model for the transmission of the fragile X dynamic repeat mutation
Authors: HUGGINS R. M. , LOESCH D. Z. , SHERMAN S. L.
Published: March 2003

A non‐linear time series version of a model for the transmission of fragile X previously described in Ashley & Sherman (1995) is developed. The model retains the biological features of the Ashley/Sherman model but is easier to generalize and in particular allows the inclusion of covariates such as haplotype to model different paths and random effects to model family effects. The model is fitted to data from Murray et al. (1997) and its properties are illustrated in a simulation study.
Statistically robust approaches for sib‐pair linkage analysis
Authors: WANG J. , GUERRA R. , COHEN J.
Published: March 2003

Many traits that distinguish one individual from another, such as height or weight, are clearly heritable and yet vary continuously in populations. Continuous, heritable variation in trait levels presumably reflects the segregation of multiple genes, but elucidation of the genetic architecture of quantitative traits has been limited. Haseman & Elston (1972) developed a genetically robust method (HE) for detecting linkage to quantitative trait loci using sib‐pairs. The method is based on a simple linear regression of the squared sib‐pairs trait difference on the proportion of alleles shared identical by descent at a marker locus. Linkage is detected by a negative slope which has been traditionally assessed by a standard t‐test. Wan, Cohen & Guerra (1997) have shown that the standard t‐test is robust to the violations of the stochastic assumptions underlying the test. In practice, however, the standard t‐test, based on least‐squares regression, is sensitive to outliers. The presence of outliers in the data can lead to false positive and false negative linkage results. Accordingly we have developed and evaluated a statistically robust procedure for the HE approach to linkage. The procedure is based on robust regression. Simulation studies show that this robust procedure has greater power than the standard t‐test in the presence of outliers, and has similar power to the standard t‐test in the absence of outliers. This robust procedure also shows greater power than rank‐based approaches either in the absence or presence of outliers. To illustrate the methods using real data we reanalyse data from two lipoprotein systems that motivated this work.
Penrose and sib‐pairs
Authors: EDWARDS J. H.
Published: March 2003

Penrose's sib‐pair papers (1935–1953) are discussed in relation to recent applications. His essential contribution that parental typing was an inefficient addition to sib‐pair data for linkage detection remains. Parents now have even less to offer with contemporary markers in the detection of linkage, although not the enumeration of haplotypes. Attention is drawn to two little known papers by Penrose on multifactorial disease, and it is suggested that this term should replace polygenic in relation to family analyses. The convention established by Penrose, both as author and editor, of raw data being published alongside its analysis, which later fell into disuse on grounds of sheer bulk, can now be remedied by the Internet, and has been for the largest set of sib‐pair data on diabetes (Davies et al. Nature371 (1994), 130–136). This is essential if the contributions to the identity and location of alleles possibly relevant to common disorders, none of which are likely to be more than suggestive in any single study, can be combined to assess consistency and joint evidence. Attention is drawn to a third little known paper by Penrose of high relevance to the strategy of familial investigations in multifactorial disorders. All five of the Penrose papers discussed here can be viewed at http://www.gene.ucl.ac.uk/anhumgen/
Mutation analysis of a putative sialyltransferase gene, the SFRS2 splicing factor gene and the c‐myb ET‐locus in two families with hereditary neuralgic amyotrophy (HNA)
Authors: KUHLENBAEUMER G. , MEULEMAN J. , SCHIRMACHER A. , STOEGBAUER F. , RINGELSTEIN E. B. , WEHNERT M. , HOELTZENBEIN M. , VAN BROECKHOVEN C. , TIMMERMAN V.
Published: March 2003

HNA is an autosomal dominant recurrent focal neuropathy involving the brachial plexus. The etiology of HNA is unknown but the genetic defect most likely affects a non‐neuronal tissue. We previously described linkage to chromosome 17q24–q25 in two HNA‐families. Here we report the mutation analysis of two candidate genes: a cDNA encoding a putative sialyltransferase and the SFRS2 splicing factor including the c‐myb ET‐locus which is encoded on the opposite strand of the SFRS2 gene. The complete protein coding regions of both genes were studied by direct DNA sequencing. We did not find a disease associated mutation indicating that these genes are most likely not involved in the pathogenesis of HNA. However, we identified and characterized a rare AvaII polymorphism in the SFRS2 gene and detected a sequencing error, leading to an amino acid change (Val11Leu) in the published sequence of the putative sialyltransferase.
Major congenital malformations in United Arab Emirates (UAE): need for genetic counselling
Authors: AL TALABANI J. , SHUBBAR A. I. , MUSTAFA K. E.
Published: March 2003

Between January 1992 and January 1995 a total of 24233 babies born consecutively in Corniche Hospital which is the only maternity hospital in Abu Dhabi, the capital of UAE, were surveyed for the presence of major congenital malformations. A total of 401 infants (16.6/1000) had a major defect. Of these malformations, 267 (67%) were associated with an estimated recurrence risk greater than 1%, and 95 (24%) carried an estimated recurrence risk greater than 10%. This included a total of 91 cases of single gene disorders and 4 cases of cleft lip and palate where a mother and another sibling were affected putting their estimated recurrence risk in the high category group. When antenatal diagnosis is feasible, this should be considered in 60% of mothers (a total of 242). In 59% (a total of 237) the estimated recurrence risk was >1% and the antenatal diagnosis of the disorder was possible. The importance of Genetic Counselling is revealed in our study since more than three quarters of mothers were under 36 years old, and may well plan future pregnancies.
Linkage disequilibrium at the cystathionine β synthase (CBS) locus and the association between genetic variation at the CBS locus and plasma levels of homocysteine
Authors: De STEFANO V. , DEKOU V. , NICAUD V. , CHASSE J. F. , LONDON J. , STANSBIE D. , HUMPHRIES S. E. , GUDNASON V. ,   on behalf of the EARS II group
Published: March 2003

Cystathionine β synthase (CBS) is a key enzyme in homocysteine metabolism. We have examined four apparently non‐functional polymorphisms in the CBS gene and have determined their frequency, degree of linkage disequilibrium and association with plasma homocysteine levels. The polymorphisms are a 68 bp insertion in exon 8, C699T in exon 8, C1080T in exon 11 and C1985T in the 3′ untranslated region. 785 individuals participating in the European Atherosclerosis Research Study II (EARSII), from 11 countries across Europe were genotyped for these polymorphisms. The 68bp insertion had the highest frequency in the UK and in the Middle region, with a lower frequency in the Baltic and the South (p=0.01), and the exon 11 polymorphism had the highest frequencies of the rare allele in the Baltic (p<0.05). There was a high degree of linkage disequilibrium between the polymorphisms (p<0.001 overall), except between C699T and the C1985T, with three common haplotypes accounting for nearly 80% of chromosomes. Examination of the association between these polymorphisms and plasma homocysteine levels revealed that the carriers of the rare alleles of the C699T, C1080T and C1985T polymorphisms had lower plasma homocysteine concentrations than those homozygous for the common alleles, although these differences were not statistically significant. The thermolabile valine variant caused by a substitution of a C for a T at nucleotide 677 in the methylenetetrahydrofolate reductase (MTHFR) has previously been shown to have profound effects on plasma levels of homocysteine in this sample, but the homocysteine‐raising effect associated with this thermolabile variant was not seen in carriers of the 68 bp insertion, with this interaction being statistically significant (p<0.001). These data demonstrate that variation in the CBS gene as detected with these four polymorphisms, had no statistically significant effect on plasma homocysteine levels in these healthy young men. However, the presence of the 68 bp insertion, which is found in approximately 7.5% of individuals in the populations of Europe sampled, abolishes the raising effect of thermolabile MTHFR Val/Val genotype, and may be of importance in the situation of high homocysteine.
Segregation analysis of squamous cell carcinoma of the head and neck: evidence for a major gene determining risk
Authors: DE ANDRADE M. , AMOS C. I. , FOULKES W. D.
Published: March 2003

We and others have shown that a family history of squamous cell carcinoma of the head and neck (SCCHN) is a risk factor for this disease. We performed a segregation analysis on a dataset comprised of 1429 first‐degree relatives of 242 unselected cases of SCCHN and 934 first‐degree relatives of 156 spouse controls. Using the SAGE software, we demonstrated that a Mendelian model was favored and a model postulating a purely environmental cause of SCCHN was rejected. The model suggests that 18% of the population who smoke and drink are susceptible. The lifetime risk for non‐smokers and non‐drinkers who are heterozygotes for the susceptible allele is close to zero, but for those heterozygotes who smoke and drink the risk is 14% by age 70. These findings suggest that specific genetic factors account for a significant fraction of the risk of SCCHN associated with a family history of SCCHN.
Mucopolysaccharidosis type I: characterization of a common mutation that causes Hurler syndrome in Moroccan subjects
Authors: ALIF N. , HESS K. , STRACZEK J. , SEBBAR S. , N'BOU A. , NABET P. , DOUSSET B.
Published: March 2003

A group of 13 Moroccan patients with MPS I and their families, including three siblings and twin siblings, was screened for mutations of the α‐l‐iduronidase gene using fluorescence‐assisted mismatch analysis (FAMA) and cycle sequencing of PCR products. The P533R mutation, which is rare in Europeans, was identified in 92% of mutant alleles (24/26). This is the highest frequency of this mutation detected in patients with Hurler syndrome. None of the patients carried the W402X or Q70X alleles, the most common MPS I mutations in Europeans. These results suggest that the P533R mutation constitutes the genetic lesion which results in MPS I in people of Moroccan descent and provides yet more evidence for the uneven geographical distribution of mutations in MPS I.
Allelic diversity of the human plasma α(1,3)fucosyltransferase gene (FUT6)
Authors: PANG H. , KODA Y. , SOEJIMA M. , SCHLAPHOFF T. , DU TOIT E. D. , KIMURA H.
Published: March 2003

The 1080‐bp coding region of the human plasma α(1,3)fucosyltransferase gene (FUT6) was sequenced in a total of 161 individuals (322 chromosomes) drawn from three populations, involving 56 Africans (Xhosa), 52 European‐Africans of South Africa, and 53 Japanese. In addition to six reported base substitutions, eleven new base substitutions and a single base insertion were found in the coding region of the FUT6. Eleven functional and four null alleles were encountered, of which 10 alleles were novel alleles identified in this study. Two null alleles have been identified previously, whereas two novel null alleles, which contained a single base (cytosine) insertion at nucleotide 499, were found in a Xhosa population. The allelic distributions of FUT6 were different among these three populations. The heterozygosity of FUT6 was 0.860, 0.699, and 0.632, in Xhosa, European‐African (South Africa), and in Japanese populations, respectively. The extensive DNA sequence diversity of the FUT6 may be suitable for application as a tool in genetic studies for modern human evolution.
A logistic regression based extension of the TDT for continuous and categorical traits
Authors: WALDMAN I. D. , ROBINSON B. F. , ROWE D. C.
Published: March 2003

The transmission disequilibrium test (TDT), designed as a test of linkage in the presence of association (i.e. linkage disequilibrium), has received considerable attention in the recent statistical genetics literature due to its advantages over other within‐family analytic methods. One limitation of the conventional TDT is its application solely to linkage disequilibrium between a genetic marker and a single categorical trait (e.g. presence or absence of a disease). In this paper, we present an extension of the TDT using logistic regression to examine the relation between a candidate gene or genetic marker and one or more continuous or categorical explanatory variables. This logistic regression extension of the TDT possesses all of the desirable features of the conventional TDT, as well as many advantages associated with traditional regression analysis. We describe the model and its properties, as well as a number of its possible applications, and apply it to examine linkage disequilibrium between the dopamine receptor D2 gene (DRD2) and symptoms of childhood attention deficit hyperactivity disorder (ADHD). We also briefly compare the logistic regression TDT to other quantitative TDTs that have been proposed in the literature, and highlight the advantages of a regression‐based approach for examining the relation between a candidate gene and one or more continuous or categorical traits. Given its features, we regard the logistic regression extension of the TDT as a flexible new data analytic method with extensive potential applications to problems in medical, psychiatric, and behavioral genetics.
Testing the equality of twin correlations with multinomial outcomes
Authors: BARTFAY E. , DONNER A. , KLAR N.
Published: March 2003

Twin studies are widely used to study genetic and environmental influences on human measurements. Correlations are often used in such studies to compare the levels of similarity between monozygotic and dizygotic twins with respect to a specified trait. In this paper, we compare three procedures for testing the equality of twin correlations when the outcome variable of interest is multinominal. One method is a likelihood ratio test based on an underlying Dirichlet‐multinomial distribution. The second method is based on the estimated large sample variance of the estimated correlation, and the third method is based on a χ2 goodness‐of‐fit test. The results of a Monte Carlo simulation show that the three methods have similar properties if the number of twin pairs is large (> 100), and the prevalence of the underlying trait is not extreme. Otherwise, the goodness‐of‐fit approach is to be preferred. We illustrate the methods by analyzing data from a previously published smoking study.
Characterization of polymorphisms in the promoter of the human angiotensin II subtype 1 (AT1) receptor gene
Authors: ERDMANN J. , RIEDEL K. , ROHDE K. , FOLGMANN I. , WIENKER T. , FLECK E. , REGITZ‐ZAGROSEK V.
Published: March 2003

In this study eight sequence variants in the functional promoter of the human angiotensin II subtype 1 (AT1 or AGTR1) receptor gene are reported. Six of these variants are in nearly total linkage disequilibrium with each other and occur with a frequency of 15.7%. By haplotype estimation this group of eight sequence variants is characterized by only five haplotypes. There is no linkage disequilibrium between one of these haplotypes and the AT1+1166A/C variant. The finding of polymorphic sites in the functional promoter of the human AT1 locus will be beneficial to the study of the role of the AT1 receptor gene in hypertension and other cardiovascular diseases.
Superiority of Denaturing High Performance Liquid Chromatography over single‐stranded conformation and conformation‐sensitive gel electrophoresis for mutation detection in TSC2
Authors: CHOY Y. S. , DABORA S. L. , HALL F. , RAMESH V. , NIIDA Y. , FRANZ D. , KASPRZYK‐OBARA J. , REEVE M. P. , KWIATKOWSKI D. J.
Published: March 2003

We evaluated denaturing high pressure liquid chromatography (DHPLC) as a scanning method for mutation detection in TSC2, and compared it to conformation‐sensitive gel electrophoresis (CSGE) and single‐stranded conformation polymorphism analysis (SSCP). The first 20 exons of TSC2were amplified from 84 TSC patients and screened initially by CSGE and then by DHPLC. Optimization of DHPLC analysis of each exon was carried out by design of primers with minimum variation in the melting temperature of the amplicon, and titration of both elution gradient and temperature. CSGE analysis identified 40 shifts (21 unique) in the 84 patients and 20 exons. All of these variants were detected by DHPLC, and an additional 27 changes (14 unique) were identified. Overall 15 of 28 (54%) unique single base substitutions were detected by CSGE; all were detected by DHPLC. 25 definite or probable mutations were found in these 84 patients (30%) in exons 1–20 of TSC2. In a subsequent blinded analysis of 15 samples with 18 distinct TSC2 sequence variants originally detected by SSCP in another centre, all variants were detected by DHPLC except one where the variation occurred within the primer. Ten other (7 unique) sequence variants were detected in these samples which had not been detected by SSCP. Overall, 11 of 16 (69%) unique single base substitutions were detected by SSCP; all were detected by DHPLC. We conclude that DHPLC is superior to both CSGE and SSCP for detection of DNA sequence variation in TSC2, particularly for single base substitution mutations.
Evidence for a major gene accounting for mild elevation in LDL cholesterol: The NHLBI Family Heart Study
Authors: COON H. , LEPPERT M. F. , KRONENBERG F. , PROVINCE M. A. , MYERS R. H. , ARNETT D. K. , ECKFELDT J. H. , HEISS G. , WILLIAMS R. R. , HUNT S. C.
Published: March 2003

Studies of rare Mendelian disorders of low density lipoprotein cholesterol (LDL‐C) metabolism have identified specific genetic mutations in the LDL receptor and apolipoprotein B. Although these rare mutations account for a small proportion of LDL‐C variation, twin and adoption studies indicate that at least 50% of the overall LDL‐C observed variation is genetically determined. In a heterogeneous sample of 3227 subjects from the NHLBI Family Heart Study collected from four US centres, we find evidence for a common major gene accounting for mild elevations (1.25 standard deviations) in LDL‐C. The analysis favored a recessive model with a frequency of 0.52 for the gene influencing elevated LDL‐C, phenotypic means of 113 mg/dl for the normal genotypes and 146 mg/dl for the abnormal genotype, and a significant polygenic heritability. This statistically‐inferred major gene accounted for 24% of the variation in LDL‐C, with polygenes accounting for another 28% of the variation. Using parameters for major gene transmission estimated in the segregation analysis, LDL‐C showed no linkage to the LDL receptor gene (LDLR), nor to the apolipoprotein E gene (APOE), nor to the cholesterol 7α‐hydroxylase gene (CYP7A1), indicating the major gene effect influencing mild elevation in LDL‐C is not explained by any of these candidate loci.
Statistical genetic analysis of plasma levels of vitamin D: familial study
Authors: LIVSHITS G. , KARASIK D. , SEIBEL M. J.
Published: March 2003

The present study attempted to evaluate the relative importance of familial/genetic factors in interindividual variation of plasma concentrations of vitamin D (calcidiol). Ninety‐five nuclear pedigrees (187 males and 168 females, aged 18–91 and 18–86 years old respectively), from the Chuvasha Autonomy, Russia, were assessed for calcidiol and sex hormones. Age‐adjusted 25‐hydroxy‐vitamin D (25OHD) measures showed very high pair‐wise correlations between all members of families, which suggest that there may be a genetic factor transmitted within the families. To test this assumption, complex segregation analysis of non‐adjusted 25OHD data was undertaken, in which genotype‐sex specific dependence of the trait on age was incorporated. The analysis showed that some 44% of the 25OHD variance was attributable to all genetic and non‐genetic factors incorporated into the model. About 22% of the variation was accounted for by a putative major gene effect.
The additive genetic gamma frailty model for linkage analysis of age‐of‐onset variation
Authors: LI H.
Published: March 2003

Age of onset is a key factor in the linkage analysis of many complex diseases. Current methods in nonparametric linkage analysis are mainly concentrated on the affected relative pairs or affected family members with age of onset information either ignored or taken into account by specifying age‐dependent penetrances for liability classes. On the other hand, gamma frailty models were developed in the biostatistics literature to model familial aggregation of age of onset. However, these frailty models cannot be used directly for linkage analysis. This paper extends the gamma frailty model by incorporating inheritance vector information and provides a semiparametric approach for linkage testing. For a given inheritance vector at the putative disease locus, we construct an additive genetic gamma frailty for each individual within a nuclear family and use the Cox proportional hazard model to model age of onset. We derive the conditional hazard ratio parameter for sib pairs and define a likelihood ratio based LOD score statistic under our model. The EM algorithm is used for estimating the parameters and the maximum likelihood functions. Simulated data sets are used to illustrate these new statistical methods.
A CORRECTION TO TDT STATISTICS FOR MAPPING QUANTITATIVE TRAIT LOCI
Authors: Wang J. , Cohen J.
Published: March 2003

Xiong et al. (1998) proposed a general transmission disequilibrium test (TDT) for quantitative traits. Their TDT for quantitative traits permits more than one child and more than one heterozygous parent per family. This TDT is also appropriate for the situation where the trait and marker loci are at varying degrees of linkage and linkage disequilibrium. Their generalized TDT statistic for a multi‐allele marker locus may be more useful in practice. However, there are several mistakes in their mathematical presentation for this generalized TDT statistic for a multi‐allele marker locus, and it confuses readers. Here, we present a corrected TDT statistic for a multi‐allele marker locus with a clearer presentation. We hope that this new presentation will remove some confusion for readers.
Familial association of disease and the structure of trivariate distributions
Authors: HUTCHINSON T. P.
Published: March 2003

In its usual form, the multifactorial model of disease transmission assumes that the liabilities to disease have a multivariate normal distribution. This paper studies how sensitive to this assumption are the quantitative results from the model. Accordingly, bounds are established for the probability of a child having a disease, given that both parents have it and taking the heritability of the disease to be known. Unfortunately, these bounds turn out to be wide. For example, a probability that is 0.38 under the trivariate normal model may be as low as 0.12 or as high as 0.78 under other trivariate models, even if attention is restricted to those of variables‐in‐common form. The broader statistical issue of the meaning of trivariate dependence, as distinct from bivariate dependence, is also discussed.
Isolation, sequence, and chromosomal localisation of the human IκBR gene (NFKBIL2)
Authors: NORMAN D. A. M. , BARTON P. J. R.
Published: March 2003

The inhibitors of NF‐κB (IκBs) play an important role in the regulation of the NF‐κB pathway. IκBR (for IκB‐Related) is proposed to be a novel member of this family. We report the cloning and characterization of the region of the human gene encoding the previously reported mRNA. This region contains 13 exons, spread over 6550 bp of genomic sequence. The coding sequence is only weakly similar to other IκBs and the exons display a more complicated structure than has been found in other members of the IκB gene family. Moreover, the positions of intron‐exon junctions are different from those found in other IκB genes, even within the otherwise conserved ankyrin‐like repeat region, suggesting that the IκBR gene is not a member of this extended gene family. We report a revised mRNA and protein sequence for IκBR, which predicts that the protein is larger than originally described. We also report the chromosomal localisation of the human IκBR gene (approved gene symbol NFKBIL2) to 8q24.3 using PCR‐based somatic cell hybrid panel analysis and fluorescence in situ hybridization (FISH) mapping.
The FMR2 gene, FRAXE and non‐specific X‐linked mental retardation: clinical and molecular aspects
Authors: GECZ J.
Published: March 2003

FRAXE fragile site associated mental retardation remains unique among X‐linked mental retardation phenotypes due to its very mild to borderline nature (50 < IQ < 85). It is the most prevalent form of non‐specific X‐linked mental retardation so far delineated, with an estimated incidence of at least 1/50–100000 males, and with more than 50 families known worldwide. The FRAXE site is within, or immediately adjacent to, the 5′ untranslated region of the FMR2 gene. Hyperexpansion of the FRAXE CCG repeat silences transcription of the gene. The structure of FMR2 has been characterized, but its function remains unknown. Gene localizations for numerous (> 75) large families with non‐specific X‐linked mental retardation (MRX) have been determined so far. Recently the molecular basis for some of them has been unravelled by identification of the responsible genes, which participate in complex common signalling pathways. This review summarises the new data on FRAXE associated mental retardation and the FMR2 gene in the light of the recent discoveries of new genes responsible for other forms of non‐specific X‐linked mental retardation.
Human 18 kDa phosphotyrosine protein phosphatase (ACP1) polymorphism: studies of rare variants provide evidence that substitutions within or near alternatively spliced exons affect splicing result
Authors: RUDBECK L. , DISSING J. , LAZARUK K. D. A. , SENSABAUGH G.
Published: March 2003

The mammalian low molecular weight phosphotyrosine protein phosphatase is expressed as two distinct isoforms. The human ‘fast’ and ‘slow’ isoforms differ only in the sequence of an internal segment of 34 residues, and the ACP1 gene contains two adjacent exons (E3F and E3S) which encode these segments. We have previously suggested that the fast and slow isoforms are generated by mutually exclusive pre‐mRNA splicing of E3F and E3S. The common alleles ACP1*A, *B and *C express the fast and slow isoforms in different ratios. The *A and *C alleles differ from *B by C → T transitions in E3S and E3F respectively. To test the idea that the fast:slow ratio is determined by nucleotide substitutions in the E3F‐I3F‐E3S region, four groups of rare ACP1 variants with unusual fast : slow ratios and the rare *E and *R alleles, expressing fast : slow ratios similar to *C and *B, respectively, were analysed. Gene segments of the I2‐I3S region were amplified by PCR and analysed by SSCP and variant bands were excised and sequenced. For each of the rare isozymic variants one of six different nucleotide substitutions in E3F (nts+42, +85, +109, +110), I3F (nt+1) and I3S (nt+8) was observed. The *E and *R alleles showed C and B sequence, respectively, in accordance with the fast : slow ratio. The results support the hypothesis that the fast : slow ratio is constitutive.
Beta2‐adrenergic receptor allele frequencies in the Quechua, a high altitude native population
Authors: RUPERT J. L. , MONSALVE M. V. , DEVINE D. V. , HOCHACHKA P. W.
Published: March 2003

The beta2‐adrenergic receptor is involved in the control of numerous physiological processes and, as the primary catecholamine receptor in the lungs, is of particular importance in the regulation of pulmonary function. There are several polymorphic loci in the beta2‐adrenergic receptor gene that have alleles that alter receptor function, including two (A/G46, G/C79) that increase agonist sensitivity. As such a phenotype may increase vaso and bronchial dilation, thereby facilitating air and blood flow through the lungs, we hypothesized that selection may have favoured these alleles in high altitude populations as part of an adaptive strategy to deal with the hypoxic conditions characteristic of such environments. We tested this hypothesis by determining the allele frequencies for these two polymorphisms, as well one additional missense mutation (C/T491) and two silent mutations (G/A252 and C/A523) in 63 Quechua speaking natives from communities located between 3200 and 4200 m on the Peruvian altiplano. These frequencies were compared with those of two lowland populations, one native American (Na‐Dene from the west coast of Canada) and one Caucasian of Western European descent. The Quechua manifest many of the pulmonary characteristics of high altitude populations and differences in allele frequencies between the Quechua and lowlanders could be indicative of a selective advantage conferred by certain genotypes in high altitude environments. Allele frequencies varied between populations at some loci and patterns of linkage disequilibrium differed between the old‐world and new‐world samples; however, as these populations are not closely related, significant variation would be expected due to stochastic effects alone. Neither of the alleles associated with increased receptor sensitivity (A46, G79) was significantly over‐represented in the Quechua compared with either lowland group. The Quechua were monomorphic for the C allele at base 79. This variant has been associated with body mass index; however no clearly defined metabolic phenotype has been established. In addition, we sequenced the coding region of the gene in three unrelated Quechua to determine if there were any other polymorphisms common in this population. None were detected.
The effect of marker characteristics on the power to detect linkage disequilibrium due to single or multiple ancestral mutations
Authors: SHAM P. C. , ZHAO J. H. , CURTIS D.
Published: March 2003

An important design issue in allelic association studies for mapping disease genes is the choice of markers. We have used a simple model of a founder population, similar to those of Ott & Rabinowitz (1997) and Chapman & Wijsman (1998), to explore the effect of the number of alleles at a marker polymorphism on the power to detect linkage disequilibrium due to single or multiple ancestral disease mutations. We show that the optimal number of alleles is more than 2 even in the case of a single ancestral disease mutation, and much higher still if multiple ancestral mutations are present. In large samples, much power is lost by using too few alleles, but relatively little power is lost by using too many alleles. These results confirm the desirability of using highly polymorphic markers or multi‐locus haplotypes for association analysis. They also show that multiple ancestral disease mutations do not necessarily preclude linkage disequilibrium mapping, if highly polymorphic markers or multi‐locus haplotypes are used.
Association of a polymorphism at the 5′‐region of the angiotensin II type 1 receptor with hypertension
Authors: TAKAHASHI N. , MURAKAMI H. , KODAMA K. , KASAGI F. , YAMADA M. , NISHISHITA T. , INAGAMI T.
Published: March 2003

Molecular variants of individual components of the renin‐angiotensin system are thought to contribute to inherited predisposition towards essential hypertension. Using polymerase chain reaction‐denaturing gradient gel electrophoresis (PCR‐DGGE) and sequence analysis, we identified seven polymorphisms in the 5′‐flanking region of the angiotensin II type 1 receptor (AGTR1/AT1) gene. We conducted a case‐control study in a sample from the Japanese population to determine whether polymorphic markers in the 5′‐flanking region of the AT1gene were associated with essential hypertension. The study compared 149 hypertensive subjects to 156 normotensive control subjects. A significantly higher frequency of the AT1(−535)*T allele was observed in hypertensive subjects. Evidence was obtained that the AT1(−535)*T allele showed a synergistic effect on risk of hypertension with angiotensin I converting enzyme D allele (ACE*D).
Effects of age at onset on the power of the affected sib pair and transmission/disequilibrium tests
Authors: LI H. , HSU L.
Published: March 2003

Information on the age of a patient at disease onset, an important feature of complex diseases, is often collected in studies designed to map the disease genes. Penetrance‐model‐free methods, requiring no specification of penetrance functions, have been used extensively for detecting linkage and association between marker and disease loci. In this paper, we conduct an analytical study to examine the effects of incorporation of age at onset information on the power of two commonly used penetrance‐model‐free methods, the affected sib‐pair (ASP) and transmission/disequilibrium tests (TDT). Assuming a Cox model with a major gene effect for the age at onset, we quantify analytically how age at onset affects the identity by descent (IBD) probabilities, the mean IBD values, and the expected numbers of alleles transmitted from heterozygous parents to affected children under various genetic models. We show that the power of the mean IBD test and the TDT can be greatly affected by the ages at onset of affected siblings or children used in the study. Generally, the most powerful test for ASPs is that based on affected sib pairs both having early disease onset and for TDT analyses is that based on trios with early‐onset children. Naively combining affected sib pairs with different ages at onset or parent‐children trios with different ages at onset of affected children can result in reduced power for detecting linkage or association. These results may be used to guide collection and analysis of sib pairs or families for diseases with variable age at onset.
Effect of Microsomal Triglyceride Transfer Protein gene variants (−493G > T, Q95H and H297Q) on plasma lipid levels in healthy middle‐aged UK men
Authors: TALMUD P. J. , PALMEN J. , MILLER G. , HUMPHRIES S. E.
Published: March 2003

Microsomal triglyceride transfer protein (MTP) plays a central role in the synthesis of lipoproteins by shuttling lipids between phospholipid membranes to apoB. We have examined the effect of three MTP gene variants, −493G > T, Q95H and H297Q, in 2831 healthy UK middle‐aged men. The rare allele frequencies were: 0.25 (95% CI 0.24–0.26) for −493T, 0.054 (95% CI 0.05–0.06) for 95H and 0.32 (95% CI 0.31–0.33) for 297Q. The three variants were in strong allelic association in all pairwise combinations (p < 0.001). None of the variant sites were associated with significant differences in cholesterol, triglyceride, apoB or apoAI levels. When stratified by tertiles of triglycerides for the H297Q variant alone there was a significant effect on apoB levels in men in the top tertile (p= 0.01). Considering the −493G > T and H297Q genotype in combination on baseline levels, individuals with three or four rare alleles had 6.6% higher mean apoB levels compared to the rest (p= 0.007). Therefore, homozygosity for 297Q at higher triglyceride (Tg) levels, or in combination with −493G > T, is associated with a raising effect on apoB levels, suggesting the importance of modest differences in MTP activity in determining hepatic secretion of lipoproteins in healthy men.
A clinical, cytogenetic and molecular study of 47 females with r(X) chromosomes
Authors: DENNIS N. , COPPIN B. , TURNER C. , SKUSE D. , JACOBS P.
Published: March 2003

We studied 47 patients with a 45,X/46,X,r(X) karyotype to identify phenotypic differences between these patients and 45,X patients, and to determine whether these differences could be explained by the status of genes within the ring. Only 2 patients had the ‘severe’ r(X) phenotype, and both were consistent with this resulting from functional disomy of genes normally subject to X inactivation. A further 7 patients also carried active rings but these patients did not have a more severe phenotype than those whose rings were inactivated, probably because their rings were smaller and did not contain the (as yet unidentified) genes whose functional disomy is particularly damaging. Patients with a r(X) did not show clear physical differences when compared with a 45,X series, except for a possible reduction in the frequency of oedema in those whose r(X) had an Xq breakpoint distal to DXS128E, at Xq13.2. Thus some protection from oedema may be provided by the presence of two copies of Xq13.2.
Ring‐X chromosomes: their cognitive and behavioural phenotype
Authors: KUNTSI J. , SKUSE D. , ELGAR K. , MORRIS E. , TURNER C.
Published: March 2003

We tested the cognitive abilities and educational attainments of 47 patients with a ring X chromosome, to evaluate the extent to which these variables correlated with failure of r(X) inactivation and with mosaicism. We found possession of a r(X) chromosome was associated with an increased risk of significant learning difficulties, and with associated behavioural maladjustment, compared with 45,X Turner females. Nearly a third had been educated outside mainstream schools. The proportion of cells in peripheral blood containing an inactivated r(X) chromosome was negatively correlated with nonverbal IQ. The parental origin of the normal chromosome did not appear to affect adjustment or abilities. In a minority of r(X) cases associated with mental retardation, there had been a failure to inactivate the ring, due to loss of the XIST locus. However, failure of X‐inactivation was not necessarily associated with a severe phenotype. The degree of impairment in IQ depended on the size of the active ring, and hence was proportionate to the number of (as yet unidentified) genes whose functional disomy affected brain development and functioning.
Genetic diversity at the FMR1 locus in the Indonesian population
Authors: FARADZ SULTANA M. H. , PATTIIHA M. Z. , LEIGH D. A. , JENKINS M. , LEGGO J. , BUCKLEY M. F. , HOLDEN J. J. A.
Published: March 2003

We report an analysis of allelic diversity at short tandem repeat polymorphisms within the fragile XA locus in 1069 male volunteers from twelve Indonesian sub‐populations. An odd numbered allele of DXS548 was found at high frequency in all Indonesian populations. Greater allelic diversity was identified at the loci under study than has been previously reported for an Asian population. These differences distinguish the Indonesian population from all previously reported Asian, European and African populations. A high frequency of small premutation alleles, 4/120 (3.3%, 95% CI 0.9–8.3%), was identified in the Moluccan population of Hiri Island.
Linkage analysis of candidate endothelin pathway genes in nonsyndromic familial orofacial cleft
Authors: PEZZETTI F. , SCAPOLI L. , MARTINELLI M. , CARINCI F. , BRUNELLI G. , CARLS F. P. , PALOMBA F. , GOMBOS F. , CARINCI P. , TOGNON M.
Published: March 2003

There is good evidence from linkage analysis and mouse model knockouts that the endothelin‐1 gene (EDN1) is a good candidate for non‐syndromic orofacial cleft (OFC) disease. EDN1 maps to the chromosomal region of the OFC1 locus in 6p23. Therefore we have examined three other candidate genes in the endothelin pathway (ECE1, EDNRA and EDNRB, which map to chromosomes 1, 4 and 13 respectively) in a linkage study of 9 families with OFC, where the disorder is not linked to chromosome 6p23. The total lod score for these 9 multiplex families never exceeded −2.00 and thus our data suggest that EDN1 and related genes are not involved in non‐syndromic familial OFC.
A branch site mutation leading to aberrant splicing of the human tyrosine hydroxylase gene in a child with a severe extrapyramidal movement disorder
Authors: JANSSEN R. J. R. J. , WEVERS R. A. , HÄUSSLER M. , LUYTEN J. A. F. M. , STEENBERGEN‐SPANJERS G. C. H. , HOFFMANN G. F. , NAGATSU T. , VAN DEN HEUVEL L. P. W. J.
Published: March 2003

We report a branch site mutation in the gene of the enzyme tyrosine hydroxylase (TH): a −24t > a substitution two bases upstream of the adenosine in the branchpoint sequence (BPS) of intron 11. As normal lariat formation is therefore prevented, alternative splicing takes place: use of the BPS of intron 12 results in skipping of exon 12, whereas the use of a cryptic branch site in intron 11 leads to partial retention of this intron in the mRNA. This leads in both cases to an aberrant protein product. In the one case, skipping of exon 12 results in the absence of 32 amino acids. In the other, retention of 36 nucleotides of intron 11 in the mRNA results in the incorporation of twelve additional amino acids. The functional consequences of this mutation for the patient, who is also heterozygous for another previously identified mutation, become apparent in a severe clinical phenotype.