The Experts below are selected from a list of 267 Experts worldwide ranked by ideXlab platform
M G Mcinnis - One of the best experts on this subject based on the ideXlab platform.
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Linkage of bipolar affective disorder on chromosome 8q24: follow-up and parametric analysis
Molecular Psychiatry, 2004Co-Authors: D Avramopoulos, V L Willour, P P Zandi, Y Huo, D F Mackinnon, J B Potash, J R Depaulo, M G McinnisAbstract:Our group first reported a linkage finding for bipolar (BP) disorder on chromosome 8q24 in a study of 50 multiplex pedigrees, with an HLOD score reaching 2.39. Recently, Cichon et al reported an LOD score of 3.62 in the same region using two-point parametric analysis. Subsequently, we published the results of a genome scan for linkage to BP disorder using a sample extended to 65 pedigrees in which chromosome 8q24 provided the best finding, an NPL score of 3.13, approaching the accepted score for suggestive linkage. We have now fine mapped this region of chromosome 8 in our 65 pedigrees by the addition of 19 microsatellite markers reaching a marker density of 0.8 cM and an information content of 0.84. After the addition of the new data, the original NPL score slightly increased to 3.25. Two-point parametric analysis using the model employed by Cichon et al obtained an LOD score of 3.32 for marker D8S256 at θ =0.14 exceeding the proposed threshold for genomewide significance. After adjusting the parameters in accordance with the ‘Common disease–Common Variant’ hypothesis, multipoint parametric analysis resulted in an HLOD of 2.49 ( α =0.78) between D8S529 and D8S256, and defined a 1-LOD interval corresponding to a 2.3 Mb region. No allelic association with the disease was observed for our set of microsatellite markers. Biologically, plausible candidate genes in this region include thyroglobulin, KCNQ3 coding for a voltage-gated potassium channel and the gene for brain adenyl-cyclase (ADCY8).
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linkage of bipolar affective disorder on chromosome 8q24 follow up and parametric analysis
Molecular Psychiatry, 2004Co-Authors: D Avramopoulos, V L Willour, P P Zandi, Y Huo, D F Mackinnon, J B Potash, J R Depaulo, M G McinnisAbstract:Our group first reported a linkage finding for bipolar (BP) disorder on chromosome 8q24 in a study of 50 multiplex pedigrees, with an HLOD score reaching 2.39. Recently, Cichon et al reported an LOD score of 3.62 in the same region using two-point parametric analysis. Subsequently, we published the results of a genome scan for linkage to BP disorder using a sample extended to 65 pedigrees in which chromosome 8q24 provided the best finding, an NPL score of 3.13, approaching the accepted score for suggestive linkage. We have now fine mapped this region of chromosome 8 in our 65 pedigrees by the addition of 19 microsatellite markers reaching a marker density of 0.8 cM and an information content of 0.84. After the addition of the new data, the original NPL score slightly increased to 3.25. Two-point parametric analysis using the model employed by Cichon et al obtained an LOD score of 3.32 for marker D8S256 at theta=0.14 exceeding the proposed threshold for genomewide significance. After adjusting the parameters in accordance with the 'Common disease-Common Variant' hypothesis, multipoint parametric analysis resulted in an HLOD of 2.49 (alpha=0.78) between D8S529 and D8S256, and defined a 1-LOD interval corresponding to a 2.3 Mb region. No allelic association with the disease was observed for our set of microsatellite markers. Biologically, plausible candidate genes in this region include thyroglobulin, KCNQ3 coding for a voltage-gated potassium channel and the gene for brain adenyl-cyclase (ADCY8).
Christian Vaisse - One of the best experts on this subject based on the ideXlab platform.
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Emerging trends in the search for genetic Variants predisposing to human obesity.
Current opinion in clinical nutrition and metabolic care, 2003Co-Authors: Michael M. Swarbrick, Christian VaisseAbstract:PURPOSE OF REVIEW The models currently proposed for the genetic architecture of obesity are critically reviewed in the light of recent developments in the search for genetic causes of this condition. RECENT FINDINGS As for many other 'complex' diseases, most of the genetic Variants predisposing to human obesity have not yet been identified. To date, investigation of the genetic contribution to obesity has been conducted according to two main hypotheses. The Common disease/Common Variant hypothesis proposes that the genetic architecture of complex diseases (including obesity) is likely to consist of a limited number of alleles, each conferring a small increase in risk to the individual. Alternatively, it has also been proposed that complex diseases such as obesity may instead result from the effects of a large number of rare Variants, with substantial allelic heterogeneity at disease-causing loci. These two hypotheses have shaped strategies for the identification of disease genes, including the use of linkage analysis, association studies and the systematic sequencing of candidate genes. Linkage studies have recently been very successful in identifying new genes in which mutations cause rare monogenic syndromes of obesity. In Common obesity, numerous linkage and association studies have suggested that an increasing number of genetic loci could be involved. Overall, however, these studies have failed to identify the causal genetic Variants. In contrast, the direct sequencing of well-chosen candidate genes has led to the identification of numerous rare alleles causing both syndromic and Common obesity, which are less severe forms of the condition in humans. SUMMARY The genetic architecture of obesity is still a matter of debate. The previously accepted hypothesis of a small number of Common Variants has been undermined by the low reproducibility of association studies and inconsistencies among genome scans for obesity. While high-throughput association mapping of candidate regions holds some promise for the identification of Common susceptibility alleles, it must also be considered that the genetic predisposition to obesity may instead result from multiple rare Variants in a large number of genes.
D Avramopoulos - One of the best experts on this subject based on the ideXlab platform.
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Linkage of bipolar affective disorder on chromosome 8q24: follow-up and parametric analysis
Molecular Psychiatry, 2004Co-Authors: D Avramopoulos, V L Willour, P P Zandi, Y Huo, D F Mackinnon, J B Potash, J R Depaulo, M G McinnisAbstract:Our group first reported a linkage finding for bipolar (BP) disorder on chromosome 8q24 in a study of 50 multiplex pedigrees, with an HLOD score reaching 2.39. Recently, Cichon et al reported an LOD score of 3.62 in the same region using two-point parametric analysis. Subsequently, we published the results of a genome scan for linkage to BP disorder using a sample extended to 65 pedigrees in which chromosome 8q24 provided the best finding, an NPL score of 3.13, approaching the accepted score for suggestive linkage. We have now fine mapped this region of chromosome 8 in our 65 pedigrees by the addition of 19 microsatellite markers reaching a marker density of 0.8 cM and an information content of 0.84. After the addition of the new data, the original NPL score slightly increased to 3.25. Two-point parametric analysis using the model employed by Cichon et al obtained an LOD score of 3.32 for marker D8S256 at θ =0.14 exceeding the proposed threshold for genomewide significance. After adjusting the parameters in accordance with the ‘Common disease–Common Variant’ hypothesis, multipoint parametric analysis resulted in an HLOD of 2.49 ( α =0.78) between D8S529 and D8S256, and defined a 1-LOD interval corresponding to a 2.3 Mb region. No allelic association with the disease was observed for our set of microsatellite markers. Biologically, plausible candidate genes in this region include thyroglobulin, KCNQ3 coding for a voltage-gated potassium channel and the gene for brain adenyl-cyclase (ADCY8).
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linkage of bipolar affective disorder on chromosome 8q24 follow up and parametric analysis
Molecular Psychiatry, 2004Co-Authors: D Avramopoulos, V L Willour, P P Zandi, Y Huo, D F Mackinnon, J B Potash, J R Depaulo, M G McinnisAbstract:Our group first reported a linkage finding for bipolar (BP) disorder on chromosome 8q24 in a study of 50 multiplex pedigrees, with an HLOD score reaching 2.39. Recently, Cichon et al reported an LOD score of 3.62 in the same region using two-point parametric analysis. Subsequently, we published the results of a genome scan for linkage to BP disorder using a sample extended to 65 pedigrees in which chromosome 8q24 provided the best finding, an NPL score of 3.13, approaching the accepted score for suggestive linkage. We have now fine mapped this region of chromosome 8 in our 65 pedigrees by the addition of 19 microsatellite markers reaching a marker density of 0.8 cM and an information content of 0.84. After the addition of the new data, the original NPL score slightly increased to 3.25. Two-point parametric analysis using the model employed by Cichon et al obtained an LOD score of 3.32 for marker D8S256 at theta=0.14 exceeding the proposed threshold for genomewide significance. After adjusting the parameters in accordance with the 'Common disease-Common Variant' hypothesis, multipoint parametric analysis resulted in an HLOD of 2.49 (alpha=0.78) between D8S529 and D8S256, and defined a 1-LOD interval corresponding to a 2.3 Mb region. No allelic association with the disease was observed for our set of microsatellite markers. Biologically, plausible candidate genes in this region include thyroglobulin, KCNQ3 coding for a voltage-gated potassium channel and the gene for brain adenyl-cyclase (ADCY8).
Marek Kimmel - One of the best experts on this subject based on the ideXlab platform.
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Simulations provide support for the Common disease-Common Variant hypothesis.
Genetics, 2006Co-Authors: Bo Peng, Marek KimmelAbstract:The success of mapping genes involved in complex diseases, using association or linkage disequilibrium methods, depends heavily on the number and frequency of susceptibility alleles of these genes. These methods will be economically and statistically feasible if Common diseases are usually influenced by one or a few susceptibility alleles at each locus (Common disease–Common Variant, CDCV, hypothesis), but not so if there is a high degree of allelic heterogeneity. Here, we use forward-time population simulations to investigate the impact of various genetic and demographic factors on the allelic spectra of human diseases, on the basis of two models proposed by Reich and Lander and by Pritchard. Factors considered are more complex demographies, a finite-allele mutation model, population structure and migration, and interaction between disease susceptibility loci. The conclusion is that the CDCV hypothesis holds and that the phenomenon is caused by transient effects of demography (population expansion). As a result, we devise a multilocus generalization of the Reich and Lander model and demonstrate how interaction between loci with respect to their response to selection may lead to complex effects. We discuss the implications for mapping of complex diseases.
Justo Lorenzo Bermejo - One of the best experts on this subject based on the ideXlab platform.
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Comparison of six statistics of genetic association regarding their ability to discriminate between causal Variants and genetically linked markers.
Human heredity, 2011Co-Authors: Justo Lorenzo Bermejo, Kari Hemminki, Alfonso Garcia Perez, Andreas Brandt, Abigail G. MatthewsAbstract:Objectives: Genome-wide association (GWA) studies still rely on the Common-disease Common-Variant hypothesis since the assumption is associated with increased power. In GWA studies, polymorphisms are genotyped and their association with disease is investigated. Most of the identified associations are indirect and reflect a shared inheritance of the genotyped markers and genetically linked causal Variants. We have compared six statistics of genetic association regarding their ability to discriminate between markers and causal susceptibility Variants, including a probability value (Pval) and a Bayes Factor (BF) based on logistic regression, and the attributable familial relative risk (FRR). Methods: We carried out a simulation-based sensitivity analysis to explore several conceivable scenarios. Theoretical results were illustrated by established causal associations with age-related macular degeneration and by using imputed data based on HapMap for a case-control study of breast cancer. Results: Our data indicate that a representation of genetic association by FRRs and BFs generally facilitates the distinction of causal Variants. The FRR showed the best discriminative power under most investigated scenarios, but no single statistic outperformed the others in all situations. For example, rare moderate-to low-penetrance Variants (allele frequency: 1%, dominant odds ratio:
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The ‘Common Disease-Common Variant’ Hypothesis and Familial Risks
PloS one, 2008Co-Authors: Kari Hemminki, Asta Försti, Justo Lorenzo BermejoAbstract:The recent large genotyping studies have identified a new repertoire of disease susceptibility loci of unknown function, characterized by high allele frequencies and low relative risks, lending support to the Common disease-Common Variant (CDCV) hypothesis. The Variants explain a much larger proportion of the disease etiology, measured by the population attributable fraction, than of the familial risk. We show here that if the identified polymorphisms were markers of rarer functional alleles they would explain a much larger proportion of the familial risk. For example, in a plausible scenario where the marker is 10 times more Common than the causative allele, the excess familial risk of the causative allele is over 10 times higher than that of the marker allele. However, the population attributable fractions of the two alleles are equal. The penetrance mode of the causative locus may be very difficult to deduce from the apparent penetrance mode of the marker locus.