Major gene model for the inheritance of catechol-o-methyltransferase activity in five large families

Five large families including 1,189 individuals were each ascertained through one proband with essential hypertension. Four of the probands were white and one was black. Erythrocyte catechol-o-methyltransferase (COMT) activity was measured in 551 family members. Standard statistical methods were used to investigate sex, age, and family differences in COMT activity. Maximum-likelihood methods were used to fit mixtures of normal distributions to COMT activity. COMT activity is distinctly bimodal. Pedigree segregation analyses were performed on the untransformed COMT values, their square roots, and natural logarithms in each family. In no family and under none of the three transformations was it possible to reject the hypothesis of Mendelian transmission of a major gene with two alleles in Hardy-Weinberg equilibrium. In most cases a genetic hypothesis with complete dominance or recessiveness, or a hypothesis of equal transmission probabilities was rejected. While the different transformations had a large effect on the skewness and kurtosis of the overall distribution of the data, they had little effect on the outcome of these segregation analyses. Therefore, this study strongly supports the concept that variation in COMT activity is due in large part to the effects of a major gene.     

A lod score method for detecting linkage on the X chromosome between a marker locus and a major gene locus for a quantitative character

A sequential lod-score method is proposed for detecting linkage on the X chromosome between a marker locus and the locus of a major gene influencing a quantitative trait. The method uses information from sons of doubly heterozygous mothers. The average number of families required to detect linkage is substantially less than that of the fixed sample-size method proposed by Hill.Work on this article was begun while the first author was Visiting Research Fellow, Department of Psychology and Galton laboratory, University College London, 1973–1974. Preparation of this article was supported in part by grants from the Foundations Fund for Research in Psychiatry and from the National Science Foundation.     

Evidence for a major gene influencing performance on a vocabulary test

Scores on a vocabulary test given to members of 1818 nuclear families of different ethnic backgrounds were subjected to admixture analysis, segregation analysis utilizing both the mixed model and the transmission probability model and linkage analysis with 16 polymorphic markers. The data fitted a commingled distribution better than a unimodal distribution. Tests of the hypothesis that a major gene was segregating were not rejected by mixed model segregation analysis or by transmission probability analysis when provision was made for contribution from factors other than a major gene. There was no detectable heterogeneity by ethnic group nor by mating type. These analyses provide consistent support that there is a major gene for a component of verbal ability measured by a vocabulary test, and the segregation pattern is consistent with the expected Mendelian ratios. When vocabulary scores were adjusted for covariates including years of education, academic achievement, and reading habits, evidence for a major locus was lacking. The results of the linkage analysis were inconclusive. Current segregation models are affected by various factors leading to false inferences regarding monogenic mechanisms; however, in many respects, the mixed model and the transmission probability model are complementary with respect to power and robustness. The results of the analysis are discussed in this context.We thank Dr. J. M. Lalouel for access to his modified POINTER program, Professor N. E. Morton for access to NUCLEAR and POINTER, and Professor R. C. Elston for his support. The results reported here are made possible by collaboration of a group of investigators (G. C. Ashton, R. C. Johnson, M. P. Mi, and M. N. Rashad at the University of Hawaii and J. C. DeFries, G. E. McClearn, S. G. Vandenberg, and J. R. Wilson at the University of Colorado), supported by NSF Grant GB34720 and National Institute of Child Health and Human Development Grant HD06669.     

家族性高甘油三酯血症家系的候选基因位点连锁分析

目的 对一个家族性高甘油三酯血症(familial hypertriglyceridemia,FHTG)家系进行遗传连锁定位及基因突变分析.方法 32名家系成员,其中12例为高甘油三酯血症(hypertriglyceridemia)患者.应用短串联重复(short tandem repeat,STR)片段微卫星标记物对其中的22名成员进行了16个与脂代谢有关的候选基因和(或)位点的遗传连锁分析和单倍型分析,并对其中的两个候选基因APOA2和USF1直接测序以筛查突变.结果 APOA5、LIPI、RP1、APOC2、ABC1,LMF1、APOA1-APOC3-APOA4、LPL,APOB、CETP、LCAT,LDLR,APOE等候选基因位点与该家系表型不连锁,Lod值均小于-1.0(θ=0).遗传连锁分析提示位于1q23.3-24.2染色体区域,疾病表型在D1S104至D1S196之间(遗传间距为5.87 cM)存在连锁,其中D1S194两点间最大Lod值为2.44(θ=0).对APOA2和USF1基因的序列分析未发现致病突变.结论 排除了上述候选基因为本家系的致病基因;提示在1q23.3-1q24.2染色体区域可能存在一个新的与FHTG相关的基因.     

Lack of evidence of a major gene acting on postaxial polydactyly in South America

Data on polydactyly were obtained from two large samples: the Latin American Collaborative Study of Congenital Malformations (ECLAMC), and from a migrant Northeastern Brazilian population of rural origin (Hospedaria). ECLAMC is a case-control clinical epidemiological program comprising 10,035 individuals distributed among 2,030 segregating nuclear families. Hospedaria data consisted of 6,586 examined individuals belonging to 1,040 nuclear families. Using complex segregation analysis methodology we found no evidence of two loci (a major gene and a modifier locus) acting on postaxial polydactyly in the present study. Very high heritability values (in a classical multifactorial model) of postaxial polydactyly were detected, for several sets of analyses in ECLAMC and in Hospedaria. For the whole ECLAMC sample there is a peculiar suggestion of a major recessive gene effect responsible for the trait; however, no comparison with a model involving transmission probabilities (τ) was possible in this highly heterogeneous sample. If the whole ECLAMC sample is divided in subsamples, according to Black admixture proportions, the same multifactorial picture emerges. Two different inheritance patterns were verified for hand (HP) and foot (FP) postaxial polydactyly: For HP there is evidence of a non-Mendelian transmission mechanism, while for FP the parental/sib transmission appears to be due only to multifactorial causes. Am. J. Med. Genet. 80:466–472, 1998. © 1998 Wiley-Liss, Inc.     

Design and Analysis of Genetic Association Studies to Finely Map a Locus Identified by Linkage Analysis: Assessment of the Extent to Which an Association Can Account for the Linkage

Association studies are often used to finely map quantitative trait loci identified by linkage analysis. Once a polymorphism associated with the trait has been identified, it may be useful to conduct linkage analyses which adjust for this polymorphism to determine the extent to which the association accounts for the linkage signal. However, methods for conducting statistical significance tests for an observed reduction in the linkage signal are not well developed. In the present study we develop methods for assessment of the statistical significance of an observed reduction in the variance due to the linked locus, with variance components or with Haseman-Elston linkage methods. Simulations indicate that these methods have appropriate levels of type I error and that, like other association statistics, their power depends on the magnitude of linkage disequilibrium between functional and marker alleles and on the extent of similarity between the frequency of the functional allele and the frequency of the associated marker allele. These methods can help determine which association results are likely due to strong linkage disequilibrium with functional alleles and, thus, can facilitate the selection of small chromosomal regions for more extensive study.     

Lack of association between manic-depressive illness and a highly polymorphic marker from GABRA3 gene

We have carried out an association study between a dinucleotide repeat polymorphism in GABRA3 gene and manic-depressive illness in a Spanish population. This may be an important candidate gene for bipolar affective disorders since it is located in the Xq28 region, previously implicated in linkage studies. In addition, severe GABergic alterations have been reported in patients. We have not found significant differences between controls and patients in allele frequencies or genotypes. © 1995 Wiley-Liss, Inc.     

亚甲基四氢叶酸还原酶基因C677T突变与冠心病的连锁分析

目的探讨亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase, MTHFR)基因C677T突变是否与冠心病连锁。方法应用传递不平衡检验(transmission/disequilibrium test, TDT)分析了先证者一级亲属中至少有1例冠心病患者的冠心病家系45个,调查了212人。其中完整核心家系、父母一方、双方基因型缺失家系分别为21、2和22个。PCR-RFLP鉴定MTHFR基因C677T位点基因型。结果 23个核心家系经经典TDT分析,杂合子父母传递给患病子女的T等位基因频率未显著偏离50%(P＞0.05);对40个符号要求的同胞组资料的同胞传递不平衡检验(sib transmission/desequilibrium test, STDT)和同胞组不平衡检验(sibship disequilibruium test, SDT)检验均未发现受累子代与非受累子代T等位基因分布差异有显著性(P＞0.05)。结论 MTHFR基因C677T突变与冠心病不连锁,提示该位点可能不是中国人冠心病的遗传易患因子之一。     

Spondyloepiphyseal dysplasia in a cape town family: Linkage with the gene for type II collagen (COL2A1)

A moderately severe form of autosomal dominant (AD) spondyloepiphyseal dysplasia (SED) has been documented in 14 individuals in 3 generations of a family in Cape Town, South Africa. Affected persons had a short trunk; radiographic investigations indicated that skeletal involvement was worst in the hips and spine. Linkage studies with restriction fragment length polymorphisms (RFLPs) associated with the COL2A1 gene and the phenotype yielded a maximal LOD score of 4.51 at theta = 0.00. This result suggests that the structural locus for type II collagen is primarily involved in the pathogenesis of this form of SED. © 1992 Wiley-Liss, Inc.     

Linkage between serum cholinesterase 2 (CHE2) and γ-crystallin gene cluster (CRYG): assignment to chromosome 2

Serum cholinesterase 2 (CHE2) was examined in a Danish material of normal families that has been tested earlier for 70-78 classical marker systems and 25 RFLP systems. DNA for RFLP typing was provided by transforming 16-year-old frozen lymphocytes. The frequency of allele CHE2*C5+ in the Danish population was found to be 0.0430. The highest lod score was between CHE2 and the gamma-crystallin gene cluster (CRYG) (zeta = 4.21 at theta = 0.00 in females). The scores were from a single family with 15 children. CHE2 may, accordingly, be assigned to the location of CRYG: chromosome 2, bands q33-q35.     

Linkage between stature and a region on chromosome 20 and analysis of a candidate gene,bone morphogenetic protein 2

Sib-pair linkage analysis of the quantitative trait, stature, in over 500 Pima Indians indicates that a genetic determinant of governing stature is located on chromosome 20. Analysis of 10 short tandem repeat polymorphisms localized this linkage to a 3.2cM region that includes D20S98 and D20S66. Using all possible sib-pair combinations, linkage was detected to both stature (P = 0.0001) and to leg length (P = 0.001), but not to sitting height. Single-strand conformational polymorphism analysis of exon 3 of the bone morphogenetic protein 2 (BMP2) gene, a candidate gene in this region, in genomic DNA of 20 of the tallest and 20 of the shortest individuals did not show any consistent differences associated with leg length or height. Sequence analysis of the region encoding the mature protein revealed a single nucleotide substitution, a T to G transversion, not detected by single-strand conformational polymorphism (SSCP) analysis. This transversion results in a conservative amino acid substitution of glycine for valine at codon 80 of BMP2. The frequency of this allele was 0.23 in the sample. No significant differences in height were noted in persons carrying either allele. This indicates that this structural alteration in the mature BMP2 protein does not contribute to the differences in stature observed in the Pima Indians, nor is this structural change in the mature protein likely to be responsible for the linkage observed with stature on chromosome 20. © 1995 Wiley-Liss, Inc.

1 This article is a U.S. Government work and, as such, is in the public domain in the United States of America.

     

Improved typing procedure for the polymorphic single-copy RLA-DQA gene of the rabbit reveals a new allele

The DQA gene of the rabbit major histocompatibility complex (MHC, RLA) is highly polymorphic and, in contrast to those reported for other mammalian species, is present as a single copy. These properties allow use of this gene in a method to type the class II locus of RLA by a combination of single-stranded conformational polymorphism (SSCP) and heteroduplex (HD) analysis. Familial segregation of RLA-DQA was shown and RLA class II types for rabbits of unknown pedigree were determined using migration patterns of amplified genomic DNA. Typing results were confirmed in experiments where unknown samples were mixed with products from rabbits of RLA types defined by sequence analysis. These analyses detected an RLA-DQA allele in addition to the five previously described; this new allele is designated RLA-DQA-F.     

SA基因与中国汉族人群高血压病的关系

目的 探讨SA基因座是否与中国汉族人群高血压病连锁,以及SA基因多态性与中国汉族人群高血压病的关系。方法 应用MF－PCR－SSCP技术研究SA基因座微卫星的频率分布特征;以SA基因座微卫星为遗传标记,通过状态一致性受累同胞对连锁分析方法探讨SA基因座是否与高血压病连锁,运用PCR－SSCP－银染技术筛查SA基因变异体,再经测序证实,然后通过关联研究明确这种变异是否与高血压病有关。结果 （1）D16S3046、D16S3136和D16S3068多态信息量（PIC）分别为0．86、0．82和0．80,杂合度（H）分别为0．88,0．71和0．77,表明中国汉族人群SA基因座微卫星的频率分布具有高度多态性;（2）SA基因座与中国汉族人群高血压病无链关系,微卫星D16S3046、D16S3136和D16S3068连锁分析t值分别为0．972、0．622和0．236,P值分别为0．384、0．543和0．871;（3）SA基因座存在C→置换,但各基因型和等位基因的频率分布在有高血压病家族史的高血压病患者和无高血压病家族史的血压正常人之间差异无显著性,前者χ^2=0．296,P＞0．05。结论 SA基因与中国汉族人群高血压病无关,SA基因可能不是中国汉族人群高血压病的易感基因。     

EYS is a major gene for rod‐cone dystrophies in France

Autosomal‐recessive retinitis pigmentosa (arRP) was recently associated with mutations in a novel gene EYS, spanning over 2 Mb, making it the largest known gene expressed in the human eye. The purpose of this study was to establish the prevalence and nature of EYS mutations in a clinically well‐characterized cohort of 239 sporadic and arRP French cases. Direct sequencing of EYS was performed in 186 subjects for whom known mutations had previously been excluded by applying microarray technology. We mostly identified novel mutations in EYS in a total of 29 patients: Fifteen of the mutations were predicted to create premature stop codons and two represent exonic deletions. In addition, twenty missense, silent or splice‐site mutations were detected. Patients revealed homozygous or compound heterozygous mutations and in some cases, only a single mutation. Most patients showed classical signs of RP with relatively preserved central vision and visual field until late in the course of the disorder. One patient showed predominance of the disease in the inferior part of the retina suggesting potential phenotypic variability. With a prevalence of 12% or more we provide evidence that EYS is a major gene for RP in France and probably elsewhere. © 2010 Wiley‐Liss, Inc.     

Linkage and association analysis of chromosomal regions containing genes related to neuroendocrine or serotonin function in families with early-onset,recurrent major depression

Recurrent unipolar depression with an early age of onset is a severe form of unipolar depression that has both genetic and environmental components. We genotyped the members of 16 families identified by probands with early onset (⩽25 years), recurrent unipolar, major depression for 38 simple sequence tandem repeat polymorphisms (SSTRPs) from chromosomal regions containing 12 genes involved in neuroendocrine or serotonergic functioning. Pairwise linkage analysis was performed with the software package FASTLINK. The affected phenotype was defined four ways, and both dominant and recessive models of depression were analyzed. Seven SSTRPs showed lod scores >1.00 at θ values between 0.10–0.20. The members of an additional 18 families were genotyped for these seven SSTRPs, and the complete sample of 34 families was evaluated using lod score analysis, affected pedigree member linkage analysis, and within-family association analysis. Evidence for linkage between D11S929 and affective illness remained positive, necessitating the analysis of four additional SSTRPs within 3 cM of D11S929. After all confirmatory analyses were completed, no evidence suggestive of linkage remained between any of the 38 SSTRPs and the affected phenotypes. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:443–449, 1998. © 1998 Wiley-Liss, Inc.     

Linkage between severe atopy and chromosome 11q13 in Japanese families

Atopy, characterised by allergic asthma and rhinitis, is due to increased IgE responses to common aeroallergens. An Oxford group has described maternal inheritance of atopy, where there is significant linkage between IgE responsiveness and a VNTR marker D11S97 and a CA microsatellite within a candidate gene, the high affinity IgE receptor β subunit(FcεRIβ), on chromosome 11q. Attempts at independent replication have produced conflicting results. We therefore recruited 270 atopic asthmatic probands in a Japanese community population for genetic linkage analysis. Four families, each with more than 15 meioses and a clear phenotype for atopy, were selected for genetic analysis. Atopy was defined as presence of all of raised total IgE, positive RAST and skin tests to three or more aeroallergens; non-atopy, as absence of all these criteria. Linkage analysis showed a maximum two-point lod score of 9.35 for D11S97 and FcεRIβ under the assumption of unequal rates of maternal and paternal recombination. Two families showed close genetic linkage with FcεRIβ with a pattern of maternal inheritance. These results from a Japanese population provide further evidence for genetic linkage between severe atopy and chromosome 11q13 and the likelihood of genomic imprinting at the locus.     

Evidence for an autosomal recessive gene regulating the persistence of the insulin response to glucose in man

The significance of genetic factors for insulin release after glucose infusion was studied in 155 nuclear families of which 59 were control families and 96 had been ascertained through a parent with onset of diabetes after 30 years of age. Fasting insulin and glucose as well as three principal components of the insulin and glucose curves were submitted to path analysis and complex segregation analysis. The three principal components were considered to reflect the magnitude, the degree of response and the persistence of the curves. The genetic heritability of the insulin variables varied between 0.47-0.93 and that of the glucose variables between 0.20-0.54. There were considerable intergenerational differences in the genetic heritability for the persistence of the glucose curve and for the degree of response and persistence of the insulin curve. The cultural heritability was found to be of minor importance, while the non-transmitted sibling environment was large. There was significant evidence for a major locus for the persistence of the insulin curve. The best fit was for a completely recessive autosomal gene with the gene frequency 0.21. The phenotype distribution of this variable showed significant kurtosis which could simulate a major locus. However, the significant evidence for such a locus remained after an analysis using partial quantitation. The diabetics were significantly different from the non-diabetics for all the variables studied, but a complete discrimination between the diabetics and non-diabetics could not be obtained. There was no significant difference between the children of the diabetics and non-diabetics for any of the variables studied.     

Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogeneous population in Quebec points to a locus of major effect on chromosome 12q23 q24

We completed a genome-wide scan for susceptibility loci for bipolar affective disorders in families derived from a rather homogeneous population in the Province of Québec. The genetic homogeneity of this population stems from the migration of founding families into this relatively isolated area of Québec in the 1830s. A possible founder effect, combined with a prevalence of very large families, makes this population ideal for linkage studies. Genealogies for probands can be readily constructed from a population database of acts of baptism and marriage from the early 1830s up to the present time (the BALSAC register). We chose probands with a DSM III diagnosis of bipolar affective disorder and who may be grouped within large families having genealogical origins with the founding population of the Saguenay-Lac-St-Jean area. Living members (n ∼120) of a very large pedigree were interviewed using the Structured Clinical Interview for DSM III (SCID I), SCID II, and with a family history questionnaire. A diagnostic panel evaluated multisource information (interview, medical records, family history) and pronounced best-estimate consensus diagnoses on all family members. Linkage, SimAPM, SimIBD, and sib-pair analyses have been performed with 332 microsatellite probes covering the entire genome at an average spacing of 11 cM. GENEHUNTER and haplotype analyses were performed on regions of interest. Analysis of a second large pedigree in the same regions of interest permitted confirmation of presumed linkages found in the region of chromosome 12q23-q24. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:567–587, 1999. © 1999 Wiley-Liss, Inc.