Significant Genetic Linkage Research Articles

Association between 5-HT1A receptor C-1019G, 5-HTTLPR polymorphisms and panic disorder: a meta-analysis.

HTR1A C-1019G polymorphism (rs6295) and serotonin transporter promoter polymorphism (5-HTTLPR) have been linked with panic disorder (PD) in different ethnic backgrounds. Both these polymorphisms are in the promoter regions. However, results are inconsistent and contrasting evidence makes reliable conclusions even more challenging. A meta-analysis was conducted to test whether C-1019G polymorphism and 5-HTTLPR were involved in the etiology of PD. Articles researching the link between C-1019G, 5-HTTLPR polymorphisms, and PD were retrieved by database searching and systematically selected on the basis of selected inclusion parameters. 21 studies were included that examined the relationship of rs6295,5-HTTLPR polymorphisms with PD risk susceptibility (rs62957 polymorphism - 7 articles, and 5-HTTLPR polymorphism - 14 articles). A significant association was seen between the rs6295 polymorphism and PD pathogenesis, especially in Caucasian PD patients. No significant genetic linkage was found between the 5-HTTLPR polymorphism and PD. C-1019G polymorphism was involved in the etiology of PD in Caucasian patients. The 5-HTTLPR polymorphism was not a susceptibility factor of PD.

Exploring the quantitative genetics of traits associated with drought tolerance and yield in Pimpinella anisum L. under different water regimes

Genetic improvement of seed yield and drought resistance could be simultaneously gained in anise when breeding for drought resistance. Improving the water use efficiency of anise is a primary objective of anise breeding programs aimed at mitigating the impacts of drought stress. This study aimed to determine the predominant mechanisms involved in drought tolerance and investigate the genetic control of associated traits with drought tolerance and higher grain yield. According to these aims, 10 half-diallel hybrids and their five parents were evaluated in both field and greenhouse lysimetric experiments under well-watered and water deficit stress conditions. The results indicated that the inheritance of grain yield is complex and affected by water deficit stress. Similar heritability and genetic architecture were detected for flowering time and percentages of photosynthate partitioned to grain (PPPG) in both well-watered and water deficit stress treatments. Significant negative genetic correlations were observed between grain yield and flowering time, root dry mass, root diameter, root volume, root number, percentages of photosynthate partitioned to shoot, and percentages of photosynthate partitioned to root. Therefore, the selection of low values of these attributes can be used to improve grain yield under drought conditions. In contrast, a positive significant genetic linkage between grain yield and PPPG, chlorophyll content, cell membrane stability, and leaf relative water content reveal selection for high values of these attributes is favored. These attributes could be used as surrogate selection criteria in the early segregating generations. The P1 parent (early ripening parent) contained key genes associated with PPPG and drought escape. It was concluded that improvement of drought tolerance and grain yield could be simultaneously achieved in anise breeding programs.

Abstract EC101: Premature Stop Mutations In Mybphl Share The Common Pathomechanism Of Preventing Protein Incorporation Into The Cardiac Myofilament

Cardiomyopathy and arrhythmia are diseases with significant genetic linkage. Cardiac myosin binding protein-C (cMyBP-C) is a myofilament associated protein with a C-terminal composed of repeating immunoglobulin (Ig) and fibronectin III (FnIII) domains that bind to the myosin thick filaments and titin. Truncating mutations in the C-terminal of MyBP-C result in improper myofilament incorporation and degradation of the truncated protein and is a major cause of hypertrophic cardiomyopathy. Myosin-binding protein-H like ( MyBP-HL ) is a protein that was recently identified that is structurally related to MyBP-C. Both cMyBP-C and MyBP-HL contain repeated C-terminal Ig and FnIII domains that bind to myosin. MyBP-HL is different in that it is primarily expressed in the atria where it interacts with the myofilament. MyBP-HL premature stop mutations are associated with improper myofilament incorporation, and has been linked to ventricular conduction system abnormalities, atria enlargement, and dilated cardiomyopathy (DCM) in humans. The gnomAD database reports 9 stop-gain mutations for MYBPHL in humans including: Gln29, Trp54, Arg113, Tyr123, Trp158, Trp192, Lys250, Arg255 and Tyr307. Prior investigation modeled the MyBP-HL Arg255X mutation and showed no MyBP-HL localization into the myofilament. A null mouse model showed that loss of MyBP-HL resulted in arrhythmia and cardiomyopathy, similar to that observed in humans. We hypothesize that all MyBP-HL truncation mutations will share a common mechanism by failing to produce MyBP-HL that integrates into the sarcomere. We test this hypothesis by transfecting neonatal rat cardiomyocytes with MyBP-HL constructs containing these mutations. We tested Trp54, Arg113, Tyr123, Trp158, Trp192, Lys250 and Arg255 MyBP-HL mutations. We measured co-localization events between MyBP-HL mutants and MyBP-C in atrial and ventricular overexpressed cells and observed that stop gained mutations disrupt normal localization as we expected. Moreover, we tested wild-type MyBP-HL overexpression, and both showed to be able to incorporate in a similar pattern to cMyBP-C C-zone doublets. These truncating mutations in MYBP-HL may increase risk for developing arrhythmias, atria enlargement and DCM.

Antigen-driven PD-1+ TOX+ BHLHE40+ and PD-1+ TOX+ EOMES+ T lymphocytes regulate juvenile idiopathic arthritis in situ.

T lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro-inflammatory cytokines upon re-stimulation in vitro. Further, a significant genetic linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA). However, the functions of T lymphocytes in established disease remain elusive. Here we dissect the transcriptional and the clonal heterogeneity of synovial T lymphocytes in JIA patients by single-cell RNA sequencing combined with T cell receptor profiling on the same cells. We identify clonally expanded subpopulations of T lymphocytes expressing genes reflecting recent activation by antigen in situ. A PD-1+ TOX+ EOMES+ population of CD4+ T lymphocytes expressed immune regulatory genes and chemoattractant genes for myeloid cells. A PD-1+ TOX+ BHLHE40+ population of CD4+ , and a mirror population of CD8+ T lymphocytes expressed genes driving inflammation, and genes supporting B lymphocyte activation in situ. This analysis points out that multiple types of T lymphocytes have to be targeted for therapeutic regeneration of tolerance in arthritis.

A de novo missense mutation of FGFR2 causes facial dysplasia syndrome in Holstein cattle

BackgroundSurveillance for bovine genetic diseases in Denmark identified a hitherto unreported congenital syndrome occurring among progeny of a Holstein sire used for artificial breeding. A genetic aetiology due to a dominant inheritance with incomplete penetrance or a mosaic germline mutation was suspected as all recorded cases were progeny of the same sire. Detailed investigations were performed to characterize the syndrome and to reveal its cause.ResultsSeven malformed calves were submitted examination. All cases shared a common morphology with the most striking lesions being severe facial dysplasia and complete prolapse of the eyes. Consequently the syndrome was named facial dysplasia syndrome (FDS). Furthermore, extensive brain malformations, including microencephaly, hydrocephalus, lobation of the cerebral hemispheres and compression of the brain were present. Subsequent data analysis of progeny of the sire revealed that around 0.5% of his offspring suffered from FDS.High density single nucleotide polymorphism (SNP) genotyping data of the seven cases and their parents were used to map the defect in the bovine genome. Significant genetic linkage was obtained for three regions, including chromosome 26 where whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events in the germline of the sire.ConclusionsFDS is a novel genetic disorder of Holstein cattle. Mutations in the human FGFR2 gene are associated with various dominant inherited craniofacial dysostosis syndromes. Given the phenotypic similarities in FDS affected calves, the genetic mapping and absence of further high impact variants in the critical genome regions, it is highly likely that the missense mutation in the FGFR2 gene caused the FDS phenotype in a dominant mode of inheritance.

Quantitative Genetic Analysis Reveals Potential to Genetically Improve Fruit Yield and Drought Resistance Simultaneously in Coriander.

Enhancing water use efficiency of coriander (Coriandrum sativum L.) is a major focus for coriander breeding to cope with drought stress. The purpose of this study was; (a) to identify the predominant mechanism(s) of drought resistance in coriander and (b) to evaluate the genetic control mechanism(s) of traits associated with drought resistance and higher fruit yield. To reach this purpose, 15 half-diallel hybrids of coriander and their six parents were evaluated under well-watered and water deficit stressed (WDS) in both glasshouse lysimetric and field conditions. The parents were selected for their different response to water deficit stress following preliminary experiments. Results revealed that the genetic control mechanism of fruit yield is complex, variable and highly affected by environment. The mode of inheritance and nature of gene action for percent assimilate partitioned to fruits were similar to those for flowering time in both well-watered and WDS conditions. A significant negative genetic linkage was found between fruit yield and percent assimilate partitioned to root, percent assimilate partitioned to shoot, root number, root diameter, root dry mass, root volume, and early flowering. Thus, to improve fruit yield under water deficit stress, selection of low values of these traits could be used. In contrast, a significant positive genetic linkage between fruit yield and percent assimilate partitioned to fruits, leaf relative water content and chlorophyll content indicate selection for high values of these traits. These secondary or surrogate traits could be selected during early segregating generations. The early ripening parent (P1; TN-59-230) contained effective genes involved in preferred percent assimilate partitioning to fruit and drought stress resistance. In conclusion, genetic improvement of fruit yield and drought resistance could be simultaneously gained in coriander when breeding for drought resistance.

The evolutionary scope and neurological disease linkage of yeast-prion-like proteins in humans

BackgroundPrions are proteinaceous particles that propagate alternative protein conformations/states to further copies of the same proteins, and are transmitted from cell-to-cell, and organism-to-organism. Prions are usually made of the beta-sheet rich assemblies termed amyloid. The original prion protein PrP causes devastating neurodegenerative disorders in humans and other mammals. In the yeast Saccharomyces cerevisiae, many prion-forming proteins have been observed; a prominent feature of these proteins is an intrinsically disordered domain rich in glutamine (Q) and asparagine (N) residues. Several human proteins that are yeast-prion-like, in particular those with poly-glutamine (poly-Q) expansions, have been experimentally implicated in human neurodegenerative diseases.ResultsHere, we have constructed a comprehensive list of human yeast-prion-like proteins that are linked to human neurological disease. Surprisingly, different methods to annotate yeast-prion-like proteins in humans have limited intersection. However, independent of annotation method, we find that human yeast-prion-like proteins as a group have a statistically significant genetic linkage to neurological disease, that is caused specifically by linkage to neurodegenerative diseases. This is despite: (i) no especially high expression of yeast-prion-like proteins in the central nervous system, or (ii) no general enrichment of intrinsically disordered proteins in neurological/neurodegenerative diseases. Cytoskeletal proteins are significantly overrepresented in the set of human yeast-prion-like neurological proteins. Whether involved in neurological pathomechanisms or not, yeast-prion-like proteins in humans have very limited conservation outside of Deuterostomia (< ~10 %) with only a handful having prion-like character in both human and S. cerevisiae. The only such protein with a disease linkage is PUB1/TIA1, which functions as a stress granule component. Thus, the yeast-prion-like character of proteins linked to neurodegenerative diseases has not been conserved over the deep evolutionary time since the last common ancestor of yeasts and humans.ConclusionOur results provide a comprehensive picture of yeast-prion-like proteins in humans and contribute to the strategic basis for experimental investigation of the link between yeast-prion-like protein character and neurological disease.ReviewersReviewed by Istvan Simon and Alexander Schleiffer. For the full reviews, please go to the Reviewers’ comments section.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-016-0134-5) contains supplementary material, which is available to authorized users.

Contributions of Histopathology and Molecular Biology for the Discovery of Genodermatoses in Animals

Genodermatoses are dermatologic problems that are usually associated with single gene mutations and that generally exhibit Mendelian patterns of inheritance. Affected cases develop skin lesions at birth or, occasionally, before birth. To date, 2 major genodermatoses with identification of the causative gene mutations have been described in the veterinary literature: congenital ichthyosis and hereditary epidermolysis bullosa. Although many genodermatoses have been described in a variety of mammals, our knowledge of the causative genetic alterations has been extremely limited. Several molecular biology techniques have been developed and utilized to discover gene mutations in genetic disorders. Pedigree analysis is a method to study the inheritance pattern of the mutated genes (autosomal, sex linked, dominant, recessive, codominant). Segregation of gene mutations with disease phenotypes can be statistically analyzed by segregation analysis. For example, segregation ratios in autosomal recessive disorders will be close to 25%, whereas the ratios in autosomal dominant disorders will be approximately 50%. Complete pedigree and segregation analyses can be archived only if the disease phenotypes in patients are well characterized and regarded to be identical among the same group. In genodermatoses, detailed histopathologic and electron microscopic analyses of the skin lesions are generally performed to define the diseases. Identification of causative gene mutations in genetic disorders might be easier if the abnormalities in the diseases are characterized at the protein level (eg, downregulation of laminin a3 protein at the epidermal basement membrane in German Shorthaired Pointers with inherited junctional epidermolysis bullosa). However, if protein abnormalities could not be identified, positional cloning or candidate gene approaches have widely been used to identify causative genes for genetic disorders. Positional cloning is the method to identify causative genes based on their chromosomal location without protein information. This method is advantageous for discovery of causative genes in human genetic disorders but requires extensive work to define the candidate region after screening multiple genetic markers and fine mapping. Discovery of a deletion mutation in the melanophilin gene in cats with diluted hair is a good example: investigators initially screened 483 microsatellite markers in 89 cats with diluted coat color and 158 wild-type cats by whole-genome scan and found significant genetic linkage between color-dilute hair and 1 microsatellite that mapped to a gene locus close to the melanophilin gene. Alternatively, in the candidate gene approach, genes are selected based on the relationship between disease phenotype and known or predicted biological function of the translated product, knowledge of similar spontaneous diseases in other species or mouse models, or the results of linkage analysis. A disadvantage of this method might be to obtain false-positive linkage unless the disease and control groups share similar genetic background. In this issue, Mauldin et al describe a new variant of autosomal recessive congenital ichthyosis (ARCI), a group of congenital keratinization disorders, in American Bulldogs associated with deficiency of ichthyin. Ichthyin is expressed in the stratum granulosum of the epidermis, where it interacts with desmoplakin, desmosomes, and keratins, and it is speculated to be involved in lamellar body transport and formation of the stratum corneum. In this report, the investigators focused on a congenital keratinization disorder with autosomal recessive inheritance initially recognized in a single purebred dog that was suspected to have limited gene pool. Histopathologic and ultrastructural findings in this and other affected cases resembled those reported in humans with ARCI. Therefore, the investigators selected markers within 7 candidate genes that have been reported as causative genes in human ARCI, and they found that the disease was linked to NIPAL4, which encodes ichthyin. Although the investigators could not find a mutation in the open reading frame of NIPAL4, they found insertion of a small interspersed element (SINE) in the upstream region of NIPAL4. A negative effect of the SINE insertion on ichthyin expression was confirmed

Mendelian inheritance, genetic linkage, and genotypic disequilibrium at microsatellite loci in Genipa americana L. (Rubiaceae).

Genipa americana is a tropical tree species that is widely distributed in the humid tropical and subtropical regions of Central and South America. This study investigated Mendelian inheritance, genetic linkage, and genotypic disequilibrium at six microsatellite loci developed for G. americana. Adult trees (188) and regenerants (163) were sampled and genotyped in a fragmented population of the species. We also genotyped open-pollinated seeds from 12 seed-trees during reproductive events in 2010 and 2011. Significant deviations from the expected 1:1 Mendelian segregation were detected in 29.5% of the tests. Significant genetic linkage between pairwise loci was detected in 54.4% of the tests, but no genotypic disequilibrium was detected between pairwise loci for adult trees and regenerants. Overall, the results indicate that the six loci analyzed may be used in studies of G. americana's genetic diversity and structure, its mating system, and in parentage analyses.

Investigating the Mendelian inheritance, genetic linkage, and genotypic disequilibrium for ten microsatellite loci of Araucaria angustifolia

Abstract Araucaria angustifolia is a dioecious and wind pollinated conifer that typically occurs in higher attitudes of Southern Brazil. After a significant reduction of its population during the twentieth century, public policies have enabled natural populations to recover. As new studies focus on the genetics of the species it is important to investigate Mendelian inheritance, genetic linkage, and genotypic disequilibrium for the microsatellite loci developed for the species. Here we analyze ten microsatellite loci developed for A. angustifolia by genotyping 295 adult trees and 13 open pollinated progenies from a forest fragment in Santa Catarina, Brazil. The likelihood G-test shows a perfect 1:1 Mendelian segregation for all ten loci, indicating that these molecular markers are genetic markers. Significant genetic linkage between pairwise loci was detected in only 3% of the tests, suggesting that these loci are not located in the same linkage groups within the chromosomes. However, genotypic disequilibrium was detected in 51% of pairwise loci for adult trees, probably due to the strong spatial genetic structure of the population. Our results indicate that the ten loci analyzed can be used in studies on genetic diversity and structure, mating system, and gene flow of the species.

Disease penetrance of late-onset parkinsonism: a meta-analysis.

Mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13 have been implicated in late-onset familial parkinsonism. However, the estimated disease penetrance of these mutations varies widely. To compare penetrance of various mutations reported in published genetic studies to improve the understanding of late-onset parkinsonism. Forty-nine previously published studies, including 709 participants, were included for all original and subsequent articles in ISI Web of Science, PubMed electronic databases, and extracted information about number of mutation carriers within families and sporadic cases worldwide for pathogenic mutations in SNCA, LRRK2, VPS35, EIF4G1, and DNAJC13. The end-of-search date was January 31, 2014. Published studies were included if there was information on the ethnicity of the patient or unaffected individual, confirmation of mutation, age of patient or unaffected individual, age at onset, and first motor symptom of patient. Autosomal recessive parkinsonism and genes implicated without significant genetic linkage were excluded from this study. The age-associated cumulative incidence was estimated using the Kaplan-Meier method with age at onset as the time variable; asymptomatic carriers were right censored at the age at last contact or age at death. Comparative measures were obtained with log-rank tests, and each penetrance estimate was given separately with 95% confidence intervals. All the assessed autosomal dominant Parkinson disease mutations have significantly different age-dependent cumulative incidences (P < .001). In particular, penetrance of SNCA duplications was comparable to point mutations (log-rank P = .97) and driven by inclusion of SNCA p.A53T (mean age at onset, 45.9 years; 95% CI, 43-49 years). In addition, Israeli Ashkenazi Jewish LRRK2 p.G2019S carriers (mean age at onset, 57.9 years; 95% CI, 54-63 years) were comparable to Tunisian Arab Berbers (mean age at onset, 57.1 years; 95% CI, 45.5-68.7 years) (P = .58), whereas Norwegian carriers (mean age at onset, 63 years; 95% CI, 51.4-74.6 years) were significantly different from the other groups (P < .001). Parkinson disease pathogenic mutations have an age-dependent penetrance that could be ameliorated or exacerbated by modifier genes or environmental factors in different populations.

Conserved MHC Gene Orthologs Genetically Map to the Turkey MHC-B

The avian MHC-associated gene set includes orthologs to genes found throughout the human major histocompatibility complex (MHC), including some loci of the evolutionarily conserved class III region. In the turkey and other Galliformes, genes linked to the MHC have been identified because they are closely associated with class I or class II genes. This study was designed to evaluate additional class III genes for linkage to the avian MHC to further determine conservation of these loci in birds. BLAST searches were used to locate sequences in the turkey genome with similarity to genes shared between the MHC of Xenopus and humans. Primers were designed to target 25 genes, and putative orthologs were amplified by PCR and sequenced. Sequence polymorphisms were identified for 15 genes in turkey reference mapping families, and 8 genes showed significant genetic linkage to the turkey MHC-B locus. These new genetic markers and linkage relationships broaden our understanding of the composition of the avian MHC and expand the gene content for the turkey MHC-B.

New Polymorphic Microsatellite Loci for the Zebra MusselDreissena polymorpha(Pallas, 1771), a Common Bioindicator

ABSTRACT To investigate the influence of environmental pollution on the population genetics of Dreissena polymorpha, we developed five new polymorphic micro satellite loci for the zebra mussel. This mussel is widely distributed and is a common bioindicator in the field of ecotoxicology. The amplification of the microsatellite loci was tested on a single population of 24 individuals. In this population, the number of alleles per locus ranged from 3–14, and the observed heterozygosity ranged from 0.545–0.909 (mean, 0.772). All loci followed Hardy-Weinberg expectations, suggesting no evidence for null alleles. There was no significant genetic linkage disequilibrium, neither between the aforementioned loci nor between aforementioned loci and five previously published microsatellites for this species. All loci are valuable to investigate the influence of anthropogenic stressors on the bioindicator Dreissena polymorpha, and therefore on freshwater ecosystems in general.

PL.02.01 CSF biomarkers in Alzheimer's disease – use in clinical diagnosis and to monitor treatment effects

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (Ravg) and then weighted for sample size ( N[affected cases]). A permutation test was used to compute the probability of observing, by chance, each bin’s average rank (PAvgRnk) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (Pord). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both PAvgRnk and Pord<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with Pord<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

Population Genetic Analyses of Fusarium asiaticum Populations from Barley Suggest a Recent Shift Favoring 3ADON Producers in Southern China

Fusarium asiaticum is the predominant causal agent of Fusarium head blight (FHB) in southern China. The genetic diversity was assessed by analyzing 448 single-spore F. asiaticum isolates from 18 sampling sites that were 10 to 2,000 km apart, using seven highly informative variable number of tandem repeat (VNTR) markers. This analysis showed a significant degree of population subdivision (P < 0.001) among populations from upper, middle, and lower valleys of the Yangtze River, with little gene flow (Nm = 1.210). We observed a strong association between this genetic population subdivision and the mycotoxin produced. Our results show that the dramatic cline in trichothecene chemotypes may be explained by a recent and significant invasion of 3-acetyldeoxynivalenol (3ADON) producers in FHB pathogen composition in the middle valley. Using Bayesian statistics, we found a biased gene flow from 3ADON to nivalenol (NIV) populations. In addition, we observed significant genetic differentiation and linkage disequilibrium between NIV- and 3ADON-producing isolates at the same sampling sites. The impact of the changed agronomy and trade of cereal commodities on the spread of the new Fusarium population and the consequent increase of FHB observed in southern China are discussed.

An idiopathic epilepsy syndrome linked to 3q13.3‐q21 and missense mutations in the extracellular calcium sensing receptor gene

To identify the disease locus in a three-generation south Indian family having several of its members affected with idiopathic epilepsy. Genome-wide parametric linkage analysis was performed with 382 autosomal markers. Mutational analysis of the positional candidate genes in linked interval was performed by direct sequencing of genomic DNA from the proband in the family. Expression analysis in human adult brain was performed by Western blotting. A novel epilepsy genetic locus on chromosome 3q13.3-q21 was identified by linkage analysis. This locus comprises about 12 megabases of the genomic interval, with its proximal and distal genetic boundaries defined by microsatellite markers, D3S3675 and D3S1551, respectively. In this interval, we found a novel, patient-specific, missense variant, Arg898Gln, at the extracellular calcium sensing receptor (CASR), a gene belonging to the G-protein-coupled receptor family. CASR expression was detected in the temporal lobe, frontal lobe, parietal lobe, cerebellum, and hippocampus. Four additional, potentially pathogenic, missense CASR variants, Glu354Ala, Ile686Val, Ala988Val, and Ala988Gly, were observed in five individuals affected with idiopathic generalized epilepsy. A novel idiopathic epilepsy locus has been mapped on chromosome 3q13.3-q21, as evident by presence of significant genetic linkage. Identification of novel, rare missense CASR variants at evolutionary-conserved residues in epilepsy patients and CASR expression in various subregions of human brain raises an interesting possibility of involvement of CASR in pathophysiology of epileptic disorders.

Study of Toll-like receptor gene loci in sarcoidosis

Sarcoidosis is a multi-factorial systemic disease of granulomatous inflammation. Current concepts of the aetiology include interactions of unknown environmental triggers with an inherited susceptibility. Toll-like receptors (TLRs) are main components of innate immunity and therefore TLR genes are candidate susceptibility genes in sarcoidosis. Ten members of the human TLR gene family have been identified and mapped to seven chromosomal segments. The aim of this study was to investigate all known TLR gene loci for genetic linkage with sarcoidosis and to follow positive signals with different methods. We analysed linkage of TLR gene loci to sarcoidosis by use of closely flanking microsatellite markers in 83 families with 180 affected siblings. We found significant linkage between sarcoidosis and markers of the TLR4 gene locus on chromosome 9q (non-parametric linkage score 2.63, P = 0.0043). No linkage was found for the remaining TLR gene loci. We subsequently genotyped 1203 sarcoidosis patients from 997 families, 1084 relatives and 537 control subjects for four single nucleotide polymorphisms of TLR4, including Asp299Gly and Thr399Ile. This genotype data set was studied by case-control comparisons and transmission disequilibrium tests, but showed no significant results. In summary, TLR4 - w ith significant genetic linkage results - appears to be the most promising member of the TLR gene family for further investigation in sarcoidosis. However, our results do not confirm the TLR4 polymorphisms Asp299Gly and Thr399Ile as susceptibility markers. Our results rather point to another as yet unidentified variant within or close to TLR4 that might confer susceptibility to sarcoidosis.

Corticosteroid binding globulin: a new target for cortisol-driven obesity.

We present data suggesting that corticosteroid-binding globulin (CBG) may be the causal gene of a previously identified quantitative trait locus (QTL) associated with cortisol levels, fat, and muscle content in a pig intercross. Because Cbg in human and mouse maps in the region orthologous to the pig region containing this QTL, we considered Cbg as an interesting positional candidate gene because CBG plays a major role in cortisol bioavailability. Firstly, we cloned pig Cbg from a bacterial artificial chromosome library and showed by fluorescent in situ hybridization and radiation hybrid mapping that it maps on 7q26 at the peak of the QTL interval. Secondly, we detected in a subset of the pig intercross progeny a highly significant genetic linkage between CBG plasma binding capacity values and the chromosome 7 markers flanking the cortisol-associated QTL. In this population, CBG capacity is correlated positively to fat and negatively to muscle content. Thirdly, CBG capacity was three times higher in Meishan compared with Large White parental breeds and a 7-fold difference was found in Cbg mRNA expression between the two breeds. Overall, the data accumulated in this study point to Cbg gene as a key regulator of cortisol levels and obesity susceptibility.

Gene expression fingerprints in human tubulo interstitial inflammation and fibrosis as prognostic markers of disease progression

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (Ravg) and then weighted for sample size ( N[affected cases]). A permutation test was used to compute the probability of observing, by chance, each bin’s average rank (PAvgRnk) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (Pord). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both PAvgRnk and Pord<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with Pord<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part II: Schizophrenia

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.