Major recessive gene(s) with considerable residual polygenic effect regulating adult height: confirmation of genomewide scan results for chromosomes 6, 9, and 12

Segregation and linkage analyses were performed for adult height in a population of 200 Dutch families, each of which was ascertained through a proband with asthma. The best-fit model from the segregation analysis was a major recessive gene with a significant residual polygenic background. Models without a polygenic component were rejected. A genomewide scan was performed, and it confirmed previous linkage results for chromosomes 6q25 (LOD = 3.06, D6S2436), 9p1 (LOD = 2.09, D9S301), and 12q1 (LOD = 1.86, D12S375). Our results provide evidence that a combination of segregation and linkage approaches is valuable in understanding genetic determination of common complex traits.     

Evidence for two unlinked loci regulating total serum IgE levels.

Studies investigating the genetic control of total serum IgE levels are of major importance in understanding basic pathophysiologic mechanisms in atopy and asthma, since IgE levels predict onset and correlate with the clinical expression of these disorders. Previous analysis of data from 92 families, ascertained through a parent with asthma, showed evidence for recessive inheritance of high IgE levels with linkage to chromosome 5q. Since there was significant residual familial correlation in the one-locus segregation analysis, two-locus segregation and linkage analyses were performed. Segregation analyses provided evidence for a second major locus unlinked to the locus on 5q. Utilization of this two-locus model corroborates the previous evidence for linkage between this trait and markers on 5q31-q33. The LODs for the most informative marker D5S436 increased from 3.00 at 10% recombination to 4.67 at 9% recombination, when the two-locus model was used. Additional linkage studies are needed to map this second locus. These results demonstrate the importance of performing multilocus segregation and linkage analyses for quantitative traits that are related to the phenotype of a complex disorder. This approach has given further insight into the genetics of allergy and asthma by providing evidence for a two-locus model.     

Predisposition locus for major depression at chromosome 12q22-12q23.2

Major depression disorder is a common psychiatric disease with a major economic impact on society. In many cases, no effective treatment is available. The etiology of major depression is complex, but it is clear that the disease is, to a large extent, determined genetically, especially among individuals with a familial history of major depression, presumably through the involvement of multiple predisposition genes in addition to an environmental component. As a first step toward identification of chromosomal loci contributing to genetic predisposition to major depression, we have conducted a genomewide scan by using 628 microsatellite markers on 1,890 individuals from 110 Utah pedigrees with a strong family history of major depression. We identified significant linkage to major depression in males at marker D12S1300 (multipoint heterogeneity LOD score 4.6; P=.00003 after adjustment for multiple testing). With additional markers, the linkage evidence became highly significant, with the multipoint heterogeneity LOD score at marker D12S1706 increasing to 6.1 (P=.0000007 after adjustment for multiple testing). This study confirms the presence of one or more genes involved in psychiatric diseases on the q arm of chromosome 12 and provides strong evidence for the existence of a sex-specific predisposition gene to major depression at 12q22-q23.2.     

Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21-22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3-24 and 20q12.1-11.23

We have performed genetic linkage analysis in 13 large multiply affected families, to test the hypothesis that there is extensive heterogeneity of linkage for genetic subtypes of schizophrenia. Our strategy consisted of selecting 13 kindreds containing multiple affected cases in three or more generations, an absence of bipolar affective disorder, and a single progenitor source of schizophrenia with unilineal transmission into the branch of the kindred sampled. DNA samples from these families were genotyped with 365 microsatellite markers spaced at approximately 10-cM intervals across the whole genome. We observed LOD scores >3.0 at five distinct loci, either in the sample as a whole or within single families, strongly suggesting etiological heterogeneity. Heterogeneity LOD scores >3.0 in the sample as a whole were found at 1q33.2 (LOD score 3.2; P=.0003), 5q33.2 (LOD score 3.6; P=.0001), 8p22.1-22 (LOD score 3.6; P=.0001), and 11q21 (LOD score 3.1; P=.0004). LOD scores >3.0 within single pedigrees were found at 4q13-31 (LOD score 3.2; P=.0003) and at 11q23.3-24 (LOD score 3.2; P=.0003). A LOD score of 2.9 was also found at 20q12.1-11.23 within in a single family. The fact that other studies have also detected LOD scores >3.0 at 1q33.2, 5q33.2, 8p21-22 and 11q21 suggests that these regions do indeed harbor schizophrenia-susceptibility loci. We believe that the weight of evidence for linkage to the chromosome 1q22, 5q33.2, and 8p21-22 loci is now sufficient to justify intensive investigation of these regions by methods based on linkage disequilibrium. Such studies will soon allow the identification of mutations having a direct effect on susceptibility to schizophrenia.     

An indication of major genes affecting hip and elbow dysplasia in four Finnish dog populations

The aim of the study was to assess the possible existence of major genes influencing hip and elbow dysplasia in four dog populations. A Bayesian segregation analysis was performed separately on each population. In total, 34 140 dogs were included in the data set. Data were analysed with both a polygenic and a mixed inheritance model. Polygenic models included fixed and random environmental effects and additive genetic effects. To apply mixed inheritance models, the effect of a major gene was added to the polygenic models. The major gene was modelled as an autosomal biallelic locus with Mendelian transmission probabilities. Gibbs sampling and a Monte Carlo Markov Chain algorithm were used. The goodness-of-fit of the different models were compared using the residual sum-of-squares. The existence of a major gene was considered likely for hip dysplasia in all the breeds and for elbow dysplasia in one breed. Several procedures were followed to exclude the possible false detection of major genes based on non-normality of data: permuted datasets were analysed, data-transformations were applied, and residuals were judged for normality. Allelic effects at the major gene locus showed nearly to complete dominance, with a recessive, unfavourable allele in both traits. Relatively high estimates of the frequencies of unfavourable alleles in each breed suggest that considerable genetic progress would be possible by selection against major genes. However, the major genes that are possibly affecting hip and elbow dysplasia in these populations will require further study.     

Linkage analysis of adult height in a large pedigree from a Dutch genetically isolated population

Despite extensive research of genetic determinants of human adult height, the genes identified up until now allow to predict only a small proportion of the trait’s variance. To identify new genes we analyzed 2,486 genotyped and phenotyped individuals in a large pedigree including 23,612 members in 18 generations. The pedigree was derived from a young genetically isolated Dutch population, where genetic heterogeneity is expected to be low and linkage disequilibrium has been shown to be increased. Complex segregation analysis confirmed high heritability of adult height, and suggested mixed model of height inheritance in this population. The estimates of the model parameters obtained from complex segregation analysis were used in parametric linkage analysis, which highlighted three genome-wide significant and additionally at least four suggestive loci involved in height. Significant peaks were located at the chromosomal regions 1p32 (LOD score = 3.35), 2p16 (LOD score = 3.29) and 16q24 (LOD score = 3.94). For the latter region, a strong association signal (FDR q < 0.05) was obtained for 19 SNPs, 17 of them were located in the CDH13 (cadherin 13) gene of which one (rs1035569) explained 1.5% of the total height variance.     

A New Graves Disease–Susceptibility Locus Maps To Chromosome 20q11.2

The autoimmune thyroid diseases (AITDs) include two related disorders, Graves disease (GD) and Hashimoto thyroiditis, in which perturbations of immune regulation result in an immune attack on the thyroid gland. The AITDs are multifactorial and develop in genetically susceptible individuals. However, the genes responsible for this susceptibility remain unknown. Recently, we initiated a whole-genome linkage study of patients with AITD, in order to identify their susceptibility genes. We studied a data set of 53 multiplex, multigenerational AITD families (323 individuals), using highly polymorphic and densely spaced microsatellite markers (intermarker distance <10 cM). Linkage analysis was performed by use of two-point and multipoint parametric methods (classic LOD-score analysis). While studying chromosome 20, we found a locus on chromosome 20q11.2 that was strongly linked to GD. A maximum two-point LOD score of 3.2 was obtained at marker D20S195, assuming a recessive mode of inheritance and a penetrance of.3. The maximum nonparametric LOD score was 2.4 (P=.00043); this score also was obtained at marker D20S195. Multipoint linkage analysis yielded a maximum LOD score of 3.5 for a 6-cM interval between markers D20S195 and D20S107. There was no evidence for heterogeneity in our sample. In our view, these results indicate strong evidence for linkage and suggest the presence of a major GD-susceptibility gene on chromosome 20q11.2.     

A Quantitative-Trait Locus in the Human Factor XII Gene Influences Both Plasma Factor XII Levels and Susceptibility to Thrombotic Disease

One approach to the identification of genetic loci that influence complex diseases is through the study of quantitative risk factors correlated with disease susceptibility. Factor XII (FXII) plasma levels, a related phenotype correlated with thrombosis, is such a risk factor. We conducted the first genomewide linkage screen to localize genes that influence variation in FXII levels. Two loci were detected: one on chromosome 5 and another on chromosome 10 (LOD scores 4.73 and 3.53, respectively). On chromosome 5, the peak LOD score occurred in the 5q33-5ter region, near the FXII gene. Addition of a 46C/T mutation in the FXII gene increased the multipoint LOD score to 10.21 (P=3.6 x 10(-12)). A bivariate linkage analysis of FXII activity and thrombosis further improved the linkage signal (LOD = 11.73) and provided strong evidence that this quantitative-trait locus (QTL) has a pleiotropic effect on the risk of thrombosis (P=.004). Linkage analysis conditional on 46C/T indicated that this mutation alone cannot explain the chromosome 5 signal, implying that other functional sites must exist. These results represent the first direct genetic evidence that a QTL in or near the FXII gene influences both FXII activity and susceptibility to thrombosis and suggest the presence of one or more still unknown functional variants in FXII.     

Malaria in humans: Plasmodium falciparum blood infection levels are linked to chromosome 5q31-q33.

Plasmodium falciparum malaria remains a major cause of morbidity and mortality in many tropical countries, especially those in sub-Saharan Africa. Human genetic control of malaria infection is poorly understood; in particular, genes controlling P. falciparum blood infection levels remain to be identified. We recently evidenced the existence of complex genetic factors controlling blood infection levels in an urban population living in Burkina Faso. We performed, on 153 sibs from 34 families, sib-pair linkage analyses between blood infection levels and chromosome 5q31-q33, which contains numerous candidate genes encoding immunological molecules. Our results, obtained by means of the two-point Haseman-Elston (HE) method and a nonparametric (NP) approach, show linkage of parasitemia to D5S393 (P=.002) and D5S658 (P=.0004). Multipoint analyses confirmed linkage, with a peak close to D5S658 (P=.0013 and P=.0007 with the HE and NP methods, respectively). The heritability of the locus was .48, according to the two-point results, and .43, according to the multipoint results; this indicates that its variation accounted for approximately 45% of the variance of blood infection levels and that the locus plays a central role in the control of parasitemia. The identification of the gene is, therefore, of major interest in understanding the mechanisms controlling P. falciparum parasitemia.     

Genomewide scan for gout in taiwanese aborigines reveals linkage to chromosome 4q25

Gout is a disorder of uric-acid metabolism. The Pacific Austronesian population, including Taiwanese aborigines, has a remarkably high prevalence of hyperuricemia and gout, which suggests a founder effect across the Pacific region. We report here a genomewide linkage study of 21 multiplex pedigrees with gout from an aboriginal tribe in Taiwan. From observations of familial clustering, early onset of gout, and clinically severe manifestations, we hypothesized that a major gene plays a role in this trait. Using 382 random polymorphic markers spread across 22 autosomes, we demonstrated a highly significant linkage for gout at marker D4S2623 on chromosome 4q25 (P=.0002 by nonparametric linkage [the NPL(all) statistic]; empirical P=.0006; LOD=4.3, P=4.4x10-6 by logistic regression). When alcohol consumption was included as a covariate in the model, the LOD score increased to 5.66 (P=1.3x10-6). Quantitative traits, including serum uric acid and creatinine, also showed a moderate linkage to this region. To our knowledge, this is the first genome-scan report to identify a genetic locus harboring a gout-susceptibility gene.     

Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11

Rupture of intracranial aneurysms (IAs) causes subarachnoid hemorrhage, a devastating condition with high morbidity and mortality. Angiographic and autopsy studies show that IA is a common disorder, with a prevalence of 3%-6%. Although IA has a substantial genetic component, little attention has been given to the genetic determinants. We report here a genomewide linkage study of IA in 104 Japanese affected sib pairs in which positive evidence of linkage on chromosomes 5q22-31 (maximum LOD score [MLS] 2.24), 7q11 (MLS 3.22), and 14q22 (MLS 2.31) were found. The best evidence of linkage is detected at D7S2472, in the vicinity of the elastin gene (ELN), a candidate gene for IA. Fourteen distinct single-nucleotide polymorphisms (SNPs) were identified in ELN, and no obvious allelic association between IA and each SNP was observed. The haplotype between the intron-20/intron-23 polymorphism of ELN is strongly associated with IA (P=3.81x10-6), and homozygous patients are at high risk (P=.002), with an odds ratio of 4.39. These findings suggest that a genetic locus for IA lies within or close to the ELN locus on chromosome 7.     

Modifiers of heterocarpy determine capitulum size inMicroseris hybrid D 14 (Asteraceae — Lactuceae)

The proportion of the outer, “hairy” achenes in capitula of hybrid D 14 (Microseris pygmaea × M. bigelovii) is determined by the same major gene as in its sister hybrid, B 87, as shown by marker segregation. Crossover between major gene and markers shows their genetic independence. Two modifiers segregating 9:7 influence the proportion of hairies in plants homozygous for the major gene. These same modifiers (or two genes linked with them) also determine the segregation of the number of achenes per head. Most likely, the modifiers act indirectly via a residual dependence of heterocarpy on capitulum size within strict quantitative limits set by the major gene. The identification of modifiers in a polygenic system as major genes for another character acting pleiotropically supports our contention that relatively few genes interact in plant development to determine key morphological characteristics at the organismic level.     

水稻籼型光温敏核雄性不育性遗传研究

1　引　　言水稻光温敏核雄性不育性是一种典型的生态遗传现象 ,其遗传行为既受内部基因控制 ,又受外部光、温等生态因子的调节 ,还与所处的遗传背景密切相关 .前人已对农垦 5 8Ｓ及其衍生系等粳型光温敏核不育性有过较系统地研究 ,并提出一对、二对、三对和重复基因突变等多种假说[3 ,5,7～ 9] ;但对籼型及非农垦 5 8Ｓ基因源的光温敏核不育性研究较少 .本文采用极大似然法 ,对不同来源的籼型光温敏核不育性进行系统研究 ,旨在揭示其遗传本质 ,为解决两系法杂交水稻推广过程中出现的不育起点温度“漂移”等问题提供理论依据 .2　材料与方法…     

Autosomal genomic scan for loci linked to obesity and energy metabolism in Pima Indians.

An autosomal genomic scan to search for linkage to obesity and energy metabolism was completed in Pima Indians, a population prone to obesity. Obesity was assessed by percent body fat (by hydrodensitometry) and fat distribution (the ratio of waist circumference to thigh circumference). Energy metabolism was measured in a respiratory chamber as 24-h metabolic rate, sleeping metabolic rate, and 24-h respiratory quotient (24RQ), an indicator of the ratio of carbohydrate oxidation to fat oxidation. Five hundred sixteen microsatellite markers with a median spacing of 6.4 cM were analyzed, in 362 siblings who had measurements of body composition and in 220 siblings who had measurements of energy metabolism. These comprised 451 sib pairs in 127 nuclear families, for linkage analysis to obesity, and 236 sib pairs in 82 nuclear families, for linkage analysis to energy metabolism. Pointwise and multipoint methods for regression of sib-pair differences in identity by descent, as well as a sibling-based variance-components method, were used to detect linkage. LOD scores >=2 were found at 11q21-q22, for percent body fat (LOD=2.1; P=.001), at 11q23-q24, for 24-h energy expenditure (LOD=2.0; P=.001), and at 1p31-p21 (LOD=2.0) and 20q11.2 (LOD=3.0; P=.0001), for 24RQ, by pointwise and multipoint analyses. With the variance-components method, the highest LOD score (LOD=2.3 P=.0006) was found at 18q21, for percent body fat, and at 1p31-p21 (LOD=2.8; P=.0003), for 24RQ. Possible candidate genes include LEPR (leptin receptor), at 1p31, and ASIP (agouti-signaling protein), at 20q11.2.     

Assignment of a form of congenital muscular dystrophy with secondary merosin deficiency to chromosome 1q42

We have previously reported an autosomal recessive form of congenital muscular dystrophy, characterized by proximal girdle weakness, generalized muscle hypertrophy, rigidity of the spine, and contractures of the tendo Achilles, in a consanguineous family from the United Arab Emirates. Early respiratory failure resulting from severe diaphragmatic involvement was present. Intellect and the results of brain imaging were normal. Serum creatine kinase levels were grossly elevated, and muscle-biopsy samples showed dystrophic changes. The expression of the laminin-alpha2 chain of merosin was reduced on several fibers, but linkage analysis excluded the LAMA2 locus on chromosome 6q22-23. Here, we report the results of genomewide linkage analysis of this family, by use of homozygosity mapping. In all four affected children, an identical homozygous region was identified on chromosome 1q42, spanning 6-15 cM between flanking markers D1S2860 and D1S2800. We have identified a second German family with two affected children having similar clinical and histopathological features; they are consistent with linkage to the same locus. The cumulative LOD score was 3.57 (straight theta=.00) at marker D1S213. This represents a novel locus for congenital muscular dystrophy. We suggest calling this disorder "CMD1B." The expression of three functional candidate genes in the CMD1B critical region was investigated, and no detectable changes in their level of expression were observed. The secondary reduction in laminin-alpha2 chain in these families suggests that the primary genetic defect resides in a gene coding for a protein involved in basal lamina assembly.     

Ordered-subsets linkage analysis detects novel Alzheimer disease loci on chromosomes 2q34 and 15q22

Alzheimer disease (AD) is a complex disorder characterized by a wide range, within and between families, of ages at onset of symptoms. Consideration of age at onset as a covariate in genetic-linkage studies may reduce genetic heterogeneity and increase statistical power. Ordered-subsets analysis includes continuous covariates in linkage analysis by rank ordering families by a covariate and summing LOD scores to find a subset giving a significantly increased LOD score relative to the overall sample. We have analyzed data from 336 markers in 437 multiplex (>/=2 sampled individuals with AD) families included in a recent genomic screen for AD loci. To identify genetic heterogeneity by age at onset, families were ordered by increasing and decreasing mean and minimum ages at onset. Chromosomewide significance of increases in the LOD score in subsets relative to the overall sample was assessed by permutation. A statistically significant increase in the nonparametric multipoint LOD score was observed on chromosome 2q34, with a peak LOD score of 3.2 at D2S2944 (P=.008) in 31 families with a minimum age at onset between 50 and 60 years. The LOD score in the chromosome 9p region previously linked to AD increased to 4.6 at D9S741 (P=.01) in 334 families with minimum age at onset between 60 and 75 years. LOD scores were also significantly increased on chromosome 15q22: a peak LOD score of 2.8 (P=.0004) was detected at D15S1507 (60 cM) in 38 families with minimum age at onset >/=79 years, and a peak LOD score of 3.1 (P=.0006) was obtained at D15S153 (62 cM) in 43 families with mean age at onset >80 years. Thirty-one families were contained in both 15q22 subsets, indicating that these results are likely detecting the same locus. There is little overlap in these subsets, underscoring the utility of age at onset as a marker of genetic heterogeneity. These results indicate that linkage to chromosome 9p is strongest in late-onset AD and that regions on chromosome 2q34 and 15q22 are linked to early-onset AD and very-late-onset AD, respectively.     

The role of major gene in clubfoot.

The roles of major gene and multifactorial inheritance in the etiology of clubfoot (talipes equinovarus) were studied using Caucasian clubfoot families ascertained in Indiana. The method of analysis used was complex segregation analysis under the mixed model, in which five genetic parameters were examined to test hypotheses on major gene by displacement (t), degree of dominance (d), gene frequency (q), transmission probability (tau2), and multifactorial inheritance by heritability (H). The analysis showed that the segregation pattern of clubfoot in these families is best explained by assuming the action of a major gene with additional contribution of multifactorial inheritance. The estimates of the parameters under the best-fitting model were d = .82, t = 4.69, q = .030, tau2 = .50, and H = .17.     

Evidence for Mendelian inheritance of serum IgE levels in Hispanic and non-Hispanic white families.

Considerable evidence is available suggesting a significant genetic component in the pathogenesis of asthma, but the mechanism of inheritance is not well understood. The main objective of this study was to assess if total serum IgE level, a known intermediate phenotype for asthma, is under the control of a major autosomal gene. We studied nuclear families participating in the Tucson Children's Respiratory Study in Tucson and originally selected because they belonged to a health maintenance organization. One hundred twenty-five Hispanic and 673 non-Hispanic White nuclear families were eligible; 50 Hispanic families (with 191 subjects) and 241 non-Hispanic White families (with 886 subjects) were included. Prevalence of asthma, hay fever, and parental smoking was similar among eligible families who were included and those who were not. Segregation analyses using regressive models for continuous traits showed that the best fit to the data was given by a model of Mendelian codominant inheritance of a major autosomal gene associated with higher serum IgE level. Log-likelihood for this model was not significantly different from that of the best-fitting ("unrestricted") model (P = .3) and was significantly better than log-likelihood for a dominant model (P < .0001) and a recessive model (P < .0001). An environmental model showed significant departure (P < .0001) from the unrestricted model. Tests for genetic heterogeneity showed no significant difference between the two ethnic groups. The data strongly suggest that total serum IgE levels are controlled by a major autosomal codominant gene.     

Fc epsilon R1-beta polymorphism and total serum IgE levels in endemically parasitized Australian aborigines.

Endemic helminthic infection is a major public-health problem and affects a large proportion of the world's population. In Australia, helminthic infection is endemic in Aboriginal communities living in tropical northern regions of the continent. Such infection is associated with nonspecific (polyclonal) stimulation of IgE synthesis and highly elevated total serum IgE levels. There is evidence that worm-infection variance (i.e., human capacity of resistance) and total serum IgE levels may be related to the presence of a major codominant gene. The beta chain of the high-affinity IgE receptor, Fc epsilon R1-beta, has been previously identified as a candidate for the close genetic linkage of the 11q13 region to IgE responses in several populations. We show a biallelic RsaI polymorphism in Fc epsilon R1-beta to be associated with total serum IgE levels (P = .0001) in a tropical population of endemically parasitized Australian Aborigines (n = 234 subjects). The polymorphism explained 12.4% of the total residual variation in serum total IgE and showed a significant (P = .0000) additive relationship with total serum IgE levels, across the three genotypes. These associations were independent of familial correlations, age, gender, racial admixture, or smoking status. Alleles of a microsatellite repeat in intron 5 of the same gene showed similar associations. The results suggest that variation in Fc epsilon R1-beta may regulate IgE-mediated immune responses in this population.     

Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4

As with many complex genetic diseases, genome scans for prostate cancer have given conflicting results, often failing to provide replication of previous findings. One factor contributing to the lack of consistency across studies is locus heterogeneity, which can weaken or even eliminate evidence for linkage that is present only in a subset of families. Currently, most analyses either fail to account for locus heterogeneity or attempt to account for it only by partitioning data sets into smaller and smaller portions. In the present study, we model locus heterogeneity among affected sib pairs with prostate cancer by including covariates in the linkage analysis that serve as surrogate measures of between-family linkage differences. The model is a modification of the Olson conditional logistic model for affected relative pairs. By including Gleason score, age at onset, male-to-male transmission, and/or number of affected first-degree family members as covariates, we detected linkage near three locations that were previously identified by linkage (1q24-25 [HPC1; LOD score 3.25, P=.00012], 1q42.2-43 [PCAP; LOD score 2.84, P=.0030], and 4q [LOD score 2.80, P=.00038]), near the androgen-receptor locus on Xq12-13 (AR; LOD score 3.06, P=.00053), and at five new locations (LOD score > 2.5). Without covariates, only a few weak-to-moderate linkage signals were found, none of which replicate findings of previous genome scans. We conclude that covariate-based linkage analysis greatly improves the likelihood that linked regions will be found by incorporation of information about heterogeneity within the sample.