Homologous telomere association of 19q in a female with premature ovarian failure

Premature ovarian failure (POF) may be due to a variety of genetic mechanisms. We report here, for the first time, telomere association of the long arms of chromosome 19, identified at low frequency (1%) in the peripheral blood cultures of a 30-year-old female with POF. Repeat cultures identified, in addition, the presence of 16q and 22q associations at a lower frequency (0.5%). These consistent observations are suggestive of a non-random event. Their association with POF may just be coincidental or may hypothetically explain it by an abnormal mechanism of chromosome separation, a constitutional telomere anomaly or an unidentified chromosome instability disorder.     

Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene

Muscle strength is important in functional activities of daily living and the prevention of common pathologies. We describe the two-staged fine mapping of a previously identified linkage peak for knee strength on chr12q12-14. First, 209 tagSNPs in/around 74 prioritized genes were genotyped in 500 Caucasian brothers from the Leuven Genes for Muscular Strength study (LGfMS). Combined linkage and family-based association analyses identified activin receptor 1B (ACVR1B) and inhibin β C (INHBC), part of the transforming growth factor β pathway regulating myostatin - a negative regulator of muscle mass - signaling, for follow-up. Second, 33 SNPs, selected in these genes based on their likelihood to functionally affect gene expression/function, were genotyped in an extended sample of 536 LGfMS siblings. Strong associations between ACVR1B genotypes and knee muscle strength (P-values up to 0.00002) were present. Of particular interest was the association with rs2854464, located in a putative miR-24-binding site, as miR-24 was implicated in the inhibition of skeletal muscle differentiation. Rs2854464 AA individuals were ～2% stronger than G-allele carriers. The strength increasing effect of the A-allele was also observed in an independent replication sample (n=266) selected from the Baltimore Longitudinal Study of Aging and a Flemish Policy Research Centre Sport, Physical Activity and Health study. However, no genotype-related difference in ACVR1B mRNA expression in quadriceps muscle was observed. In conclusion, we applied a two-stage fine mapping approach, and are the first to identify and partially replicate genetic variants in the ACVR1B gene that account for genetic variation in human muscle strength.     

Accurate prediction of a minimal region around a genetic association signal that contains the causal variant

In recent years, genome-wide association studies have been very successful in identifying loci for complex traits. However, typically these findings involve noncoding and/or intergenic SNPs without a clear functional effect that do not directly point to a gene. Hence, the challenge is to identify the causal variant responsible for the association signal. Typically, the first step is to identify all genetic variation in the locus region, usually by resequencing a large number of case chromosomes. Among all variants, the causal one needs to be identified in further functional studies. Because the experimental follow up can be very laborious, restricting the number of variants to be scrutinized can yield a great advantage. An objective method for choosing the size of the region to be followed up would be highly valuable. Here, we propose a simple method to call the minimal region around a significant association peak that is very likely to contain the causal variant. We model linkage disequilibrium (LD) in cases from the observed single SNP association signals, and predict the location of the causal variant by quantifying how well this relationship fits the data. Simulations showed that our approach identifies genomic regions of on average ∼50 kb with up to 90% probability to contain the causal variant. We apply our method to two genome-wide association data sets and localize both the functional variant REP1 in the α-synuclein gene that conveys susceptibility to Parkinson''s disease and the APOE gene responsible for the association signal in the Alzheimer''s disease data set.     

The genetics of asthma and allergic disease: a 21st century perspective

Asthma and allergy are common conditions with complex etiologies involving both genetic and environmental contributions. Recent genome-wide association studies (GWAS) and meta-analyses of GWAS have begun to shed light on both common and distinct pathways that contribute to asthma and allergic diseases. Associations with variation in genes encoding the epithelial cell-derived cytokines, interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), and the IL1RL1 gene encoding the IL-33 receptor, ST2, highlight the central roles for innate immune response pathways that promote the activation and differentiation of T-helper 2 cells in the pathogenesis of both asthma and allergic diseases. In contrast, variation at the 17q21 asthma locus, encoding the ORMDL3 and GSDML genes, is specifically associated with risk for childhood onset asthma. These and other genetic findings are providing a list of well-validated asthma and allergy susceptibility genes that are expanding our understanding of the common and unique biological pathways that are dysregulated in these related conditions. Ongoing studies will continue to broaden our understanding of asthma and allergy and unravel the mechanisms for the development of these complex traits.     

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.     

Recurrence of the VATER association within a sibship

Two brothers with oesophageal atresia as part of the VATER association are described, the first such report of sibling recurrence with the VATER association.     

Confirmation of CHD7 as a cause of CHARGE association identified by mapping a balanced chromosome translocation in affected monozygotic twins

Background

CHARGE syndrome has an estimated prevalence of 1/10 000. Most cases are sporadic which led to hypotheses of a non‐genetic aetiology. However, there was also evidence for a genetic cause with reports of multiplex families with presumed autosomal dominant, possible autosomal recessive inheritance and concordant twin pairs. We identified a monozygotic twin pair with CHARGE syndrome and a de novo balanced chromosome rearrangement t(8;13)(q11.2;q22).

Methods

Fluorescence in situ hybridisation was performed with BAC and PAC probes to characterise the translocation breakpoints. The breakpoint on chromosome 8 was further refined using 10 kb probes we designed and produced using sequence data for clone RP11 33I11, the Primer3 website, and a long range PCR kit.

Results

BAC and PAC probe hybridisation redefined the breakpoints to 8q12.2 and 13q31.1. Probe RP11 33I11 spanned the breakpoint on chromosome 8. Using our 10 kb probes we demonstrated that the chromodomain gene CHD7 was disrupted by the translocation between exons 3 and 8.

Discussion

Identifying that the translocation breakpoint in our patients occurred between exons 3 and 8 of CHD7 suggests that disruption of this gene is the cause of CHARGE syndrome in the twins and independently confirms the role of CHD7 in CHARGE syndrome.     

Cross-reactivity between an HLA-B27-derived peptide and a retinal autoantigen peptide: a clue to major histocompatibility complex association with autoimmune disease

Statistical correlations between the expression of various HLA antigens and certain autoimmune diseases have been observed for both HLA class I and II antigens. Autoimmune diseases like spondyloarthropathies and anterior uveitis are associated with HLA-B27, but uveitis in Behçet's disease with HLA-B51. We describe a peptide from disease-associated HLA class I antigens sharing sequence homologies with a highly uveitogenic epitope from the retinal autoantigen S-antigen. S-antigen induces autoimmune uveitis in the animal model and is a major autoantigen in human disease. The HLA peptide induced uveitis in the Lewis rat and, moreover, suppressed S-antigen-induced disease when administered orally. Patients' PBL cross-reacted with the HLA- and corresponding retinal peptide, explaining the organ specificity of the disease.     

Another observation with VATER association and a complex IV respiratory chain deficiency

The VATER association of vertebral anomalies (V), anal atresia (A), esophageal atresia and/or tracheo-esophageal fistula (TE), radial and renal anomalies (R) is a common congenital association of unknown origin with probably heterogeneous causes. Here, we report on a girl presenting with pre- and postnatal growth retardation, esophageal atresia, vertebral and costal anomalies and a unilateral radial defect, consistent with the diagnosis of VATER association. In the first month of life, she presented with failure to thrive, severe episodes of hypoglycemia, liver dysfunction and high levels of lactate, which prompted us to perform metabolic screening. A complex IV respiratory chain deficiency (RCD) was diagnosed on a liver biopsy. The respiratory chain defect was not observed in skin fibroblasts. No mtDNA point mutation or deletion was identified. The girl is now 9 years old and has a normal mental development but persistent feeding difficulties and moderate hyperlactatemia. To our knowledge, this is the second report of VATER association with mitochondrial disorder. In a previous report, a VACTERL association was observed in a girl with the mitochondrial A3243G point mutation. The association of VATER phenotype with a mitochondrial disorder may be coincidental but could also suggest that the presence of multiple malformations is the result of the antenatal expression of RCD.     

Behavioral properties of saccades generated as a choice response

The behavior characterizing choice response decision-making was studied in monkeys to provide background information for ongoing neurophysiological studies of the neural mechanisms underlying saccadic choice decisions. Animals were trained to associate a specific color from a set of colored visual stimuli with a specific spatial location. The visual stimuli (colored disks) appeared briefly at equal eccentricity from a central fixation position and then were masked by gray disks. The correct target association was subsequently cued by the appearance of a colored stimulus at the fixation point. The animal indicated its choice by saccading to the remembered location of the eccentric stimulus, which had matched the color of the cue. The number of alternative associations (NA) varied from 1 to 4 and remained fixed within a block of trials. After the training period, performance (percent correct responses) declined modestly as NA increased (on average 96, 93 or 84% correct for 1, 2 or 4 NA, respectively). Response latency increased logarithmically as a function of NA, thus obeying Hick’s law. The spatial extent of the learned association between color and location was investigated by rotating the array of colored stimuli that had remained fixed during the learning phase to various different angles. Error rates in choice saccades increased gradually as a function of the amount of rotation. The learned association biased the direction of the saccadic response toward the quadrant associated with the cue, but saccade direction was always toward one of the actual visual stimuli. This suggests that the learned associations between stimuli and responses were not spatially exact, but instead the association between color and location was distributed with declining strength from the trained locations. These results demonstrate that the saccade system in monkeys also displays the characteristic dependence on NA in choice response latencies, while more basic features of the eye movements are invariant from those in other tasks. The findings also provide behavioral evidence that spatially distributed regions are established for the sensory-to-motor associations during training which are later utilized for choice decisions.     

GWAS Integrator: a bioinformatics tool to explore human genetic associations reported in published genome-wide association studies

Genome-wide association studies (GWAS) have successfully identified numerous genetic loci that are associated with phenotypic traits and diseases. GWAS Integrator is a bioinformatics tool that integrates information on these associations from the National Human Genome Research institute (NHGRI) Catalog, SNAP (SNP Annotation and Proxy Search), and the Human Genome Epidemiology (HuGE) Navigator literature database. This tool includes robust search and data mining functionalities that can be used to quickly identify relevant associations from GWAS, as well as proxy single-nucleotide polymorphisms (SNPs) and potential candidate genes. Query-based University of California Santa Cruz (UCSC) Genome Browser custom tracks are generated dynamically on the basis of users' selected GWAS hits or candidate genes from HuGE Navigator literature database (http://www.hugenavigator.net/HuGENavigator/gWAHitStartPage.do). The GWAS Integrator may help enhance inference on potential genetic associations identified from GWAS studies.     

A unifying framework for robust association testing,estimation, and genetic model selection using the generalized linear model

The analysis of genome-wide genetic association studies generally starts with univariate statistical tests of each single-nucleotide polymorphism. The standard approach is the Cochran-Armitage trend test or its logistic regression equivalent although this approach can lose considerable power if the underlying genetic model is not additive. An alternative is the MAX test, which is robust against the three basic modes of inheritance. Here, the asymptotic distribution of the MAX test is derived using the generalized linear model together with the Delta method and multiple contrasts. The approach is applicable to binary, quantitative, and survival traits. It may be used for unrelated individuals, family-based studies, and matched pairs. The approach provides point and interval effect estimates and allows selecting the most plausible genetic model using the minimum P-value. R code is provided. A Monte-Carlo simulation study shows that the asymptotic MAX test framework meets type I error levels well, has good power, and good model selection properties for minor allele frequencies ≥0.3. Pearson''s χ²-test is superior for lower minor allele frequencies with low frequencies for the rare homozygous genotype. In these cases, the model selection procedure should be used with caution. The use of the MAX test is illustrated by reanalyzing findings from seven genome-wide association studies including case–control, matched pairs, and quantitative trait data.     

Investigation into the Ability of SNP Chipsets and Microsatellites to Detect Association with a Disease Locus

We wished to investigate the ability of different SNP chipsets to detect association with a disease and to investigate the linkage disequilibrium (LD) relationships between microsatellites and nearby SNPs in order to assess their potential usefulness to detect association.
SNP genotypes were obtained from HapMap and microsatellite genotypes from CEPH. 5000 SNPs were simulated as disease genes which increased penetrance from 0.01 to 0.02 in a sample of 400 cases and 400 controls. The power of flanking SNPs to detect association was tested using sets of 1, 2, 3 or 4 markers analysed with haplotype analysis or logistic regression and using either all HapMap markers or those from the Affymetrix 500K, Illumina 300K or Illumina 550K chipsets. Additionally, LD relationships between 10 microsatellites and SNPs within 2Mb of each other were studied.
The power for one of the markers to detect association at p = 0.001 was around 0.4. Power was slightly better for logistic regression than haplotype analysis and for two-marker as opposed to single marker analysis but analysing with larger numbers markers had little benefit. The Illumina 550K marker set was better able to detect association than the other two and was almost as powerful as using all HapMap markers. Microsatellites had detectable LD with only a small number of nearby SNPs and the pattern of LD was very variable.
Available chipsets have quite good ability to detect association although obviously results will be critically dependent on the nature of the genetic effect on risk, sample size and the actual LD relationships of the susceptibility polymorphisms involved. Microsatellites seem ill-suited for systematic studies to detect association.     

The etiology of VACTERL association: Current knowledge and hypotheses

VACTERL association is a condition involving the presence of multiple congenital anomalies. The condition was first described more than four decades ago, and is not extremely rare. However, relatively little is understood about the causes and underlying biology of the condition as a whole. There are many reasons for this, but there is increasing recognition that VACTERL is extremely clinically as well as etiologically heterogeneous, and this heterogeneity––as well as other hypothesized factors––have caused challenges to identifying the causes for a substantial proportion of patients. Current knowledge about the causes of this condition (or group of conditions) are described, followed by a discussion of possibilities that may reveal more answers for patients as well as researchers and clinicians who work related to this disorder.     

Whole genome survey of coding SNPs reveals a reproducible pathway determinant of Parkinson disease

It is quickly becoming apparent that situating human variation in a pathway context is crucial to understanding its phenotypic significance. Toward this end, we have developed a general method for finding pathways associated with traits that control for pathway size. We have applied this method to a new whole genome survey of coding SNP variation in 187 patients afflicted with Parkinson disease (PD) and 187 controls. We show that our dataset provides an independent replication of the axon guidance association recently reported by Lesnick et al. [PLoS Genet 2007;3:e98], and also indicates that variation in the ubiquitin-mediated proteolysis and T-cell receptor signaling pathways may predict PD susceptibility. Given this result, it is reasonable to hypothesize that pathway associations are more replicable than individual SNP associations in whole genome association studies. However, this hypothesis is complicated by a detailed comparison of our dataset to the second recent PD association study by Fung et al. [Lancet Neurol 2006;5:911-916]. Surprisingly, we find that the axon guidance pathway does not rank at the very top of the Fung dataset after controlling for pathway size. More generally, in comparing the studies, we find that SNP frequencies replicate well despite technologically different assays, but that both SNP and pathway associations are globally uncorrelated across studies. We thus have a situation in which an association between axon guidance pathway variation and PD has been found in 2 out of 3 studies. We conclude by relating this seeming inconsistency to the molecular heterogeneity of PD, and suggest future analyses that may resolve such discrepancies.     

Identification of a BglI polymorphism of Catechol-O-methyltransferase (COMT) gene,and association study with schizophrenia

Several linkage studies suggested chromosome 22q11–13 may harbor susceptible genes for schizophrenia. Catechol-O-methyl-transferase (COMT), which is involved in the metabolism of catecholamines, was mapped to 22q11 and is considered a possible candidate gene for schizophrenia. Recently, we identified a polymorphic marker, a single nucleotide C insertion at the 3′ untranslated region of the COMT gene, which obliterates a BglI site. Using this BglI polymorphism, we conducted a case-control association study in Chinese patients with schizophrenia. No significant differences of allele and genotype frequencies were noted between patients (N = 177) and controls (N = 99). When patients were subgrouped according to sex, no significant differences of genotype and allele frequencies were noted in either male or female patients compared to normal controls. Our results do not support an association between the BglI polymorphism of COMT gene and schizophrenia. © 1996 Wiley-Liss, Inc.     

Identification of a new HLA-DRB1*04 allele, DRB1*0437

In this report we describe the identification of a novel DRB1*04 allele, DRB1*0437, found in a Spanish individual. The routine HLA typing, in the context of bone marrow transplantation, by polymerase chain reaction-sequence-based typing (PCR-SBT) made possible the identification of this new allele. This allele is identical to DRB1*0402 except for a single nucleotide substitution at position 286 (A-->C), changing the encoded Isoleucine to a Leucine. The DRB1*0437 allele conserves the same two acidic residues at codons 70 and 71 that confer to DRB1*0402 its association to some autoimmune diseases.