Replication of Linkage Studies of Complex Traits: An Examination of Variation in Location Estimates

Roberts, Seth B.; Maclean, Charles; Neale, Michael C.; Eaves, Lindon J.; Kendler, Kenneth S.

doi:10.1086/302528

Cited by 256 publications

(200 citation statements)

References 25 publications

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“…This indicates the uncertainty in the location estimate for the underlying gene. Confidence intervals for the location of the susceptibility gene have been examined by modelling for affected sib-pairs [106,107] and for family studies [108][109][110]. These intervals are often surprisingly large, i.e.…”

Section: Discussionmentioning

confidence: 99%

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Lillioja

Wilton

2009

Diabetologia

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Aims/hypothesis Little of the genetic basis for type 2 diabetes has been explained, despite numerous genetic linkage studies and the discovery of multiple genes in genome-wide association (GWA) studies. To begin to resolve the genetic component of this disease, we searched for sites at which genetic results had been corroborated in different studies, in the expectation that replication among studies should direct us to the genomic locations of causative genes with more confidence than the results of individual studies. Methods We have mapped the physical location of results from 83 linkage reports (for type 2 diabetes and diabetes precursor quantitative traits [QTs, e.g. plasma insulin levels]) and recent large GWA reports (for type 2 diabetes) onto the same human genome sequence to identify replicated results in diabetes genetic 'hot spots'. Results Genetic linkage has been found at least ten times at 18 different locations, and at least five times in 56 locations. All replication clusters contained study populations from more than one ethnic background and most contained results for both diabetes and QTs. There is no close relationship between the GWA results and linkage clusters, and the nine best replication clusters have no nearby GWA result. Conclusions/interpretation Many of the genes for type 2 diabetes remain unidentified. This analysis identifies the broad location of yet to be identified genes on 6q, 1q, 18p, 2q, 20q, 17pq, 8p, 19q and 9q. The discrepancy between the linkage and GWA studies may be explained by the presence of multiple, uncommon, mildly deleterious polymorphisms scattered throughout the regulatory and coding regions of genes for type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Lillioja

Wilton

2009

Diabetologia

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“…Indeed, studies vary in terms of sampling, diagnostic and statistical methods as well as in terms of the genetic markers used. 53,54 It is then difficult to determine the extent to which linkage signals reported in the same chromosomal area in different studies represent a true replication.…”

Section: Discussionmentioning

confidence: 99%

Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families

et al. 2004

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The goal of this study was to identify susceptibility loci shared by schizophrenia (SZ) and bipolar disorder (BP), or specific to each. To this end, we performed a dense genome scan in a first sample of 21 multigenerational families of Eastern Quebec affected by SZ, BP or both (N ¼ 480 family members). This probably constitutes the first genome scan of SZ and BP that used the same ascertainment, statistical and molecular methods for the concurrent study of the two disorders. We genotyped 607 microsatellite markers of which 350 were spaced by 10 cM and 257 others were follow-up markers in positive regions at the 10 cM scan. Lander and Kruglyak thresholds were conservatively adjusted for multiple testings. We maximized the lod scores (mod score) over eight combinations (2 phenotype severity levels Â 2 models of transmission Â 2 analyses, affected/unaffected vs affected-only). We observed five genomewide significant linkages with mod score 44.0: three for BP (15q11.1, 16p12.3, 18q12-q21) and two for the shared phenotype, that is, the common locus (CL) phenotype (15q26,18q12-q21). Nine mod scores exceeded the suggestive threshold of 2.6: three for BP (3q21, 10p13, 12q23), three for SZ (6p22, 13q13, 18q21) and three for the CL phenotype (2q12.3, 13q14, 16p13). Mod scores 41.9 might represent confirmatory linkages of formerly reported genomewide significant findings such as our finding in 6p22.3 for SZ. Several regions appeared to be shared by SZ and BP. One linkage signal (15q26) appeared novel, whereas others overlapped formerly reported susceptibility regions. Despite the methodological limitations we raised, our data support the following trends: (i) results from several genome scans of SZ and BP in different populations tend to converge in specific genomic regions and (ii) some of these susceptibility regions may be shared by SZ and BP, whereas others may be specific to each. The present results support the relevance of investigating concurrently SZ and BP within the same study and have implications for the modelling of genetic effects. Molecular Psychiatry (2005) 10, 486-499.

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“…2 However, these regions are often broad and may contain several candidate genes. 3 Thus, to speed up the selection of candidate genes within these regions of interest, we combined the genetic map information with gene expression profiling data. This strategy results from two major observations: (i) the expression of numerous genes is modified during AD aetiology, [4][5][6][7][8] (ii) polymorphisms within promoters of the APOE, PS1, PS2 and APP genes have been associated with the occurrence of AD.…”

Section: Introductionmentioning

confidence: 99%

Evidence for induction of the ornithine transcarbamylase expression in Alzheimer's disease

et al. 2007

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To more rapidly identify candidate genes located within chromosomal regions of interest defined by genome scan studies in Alzheimer's disease (AD), we have developed a customized microarray containing all the ORFs (n = 2741) located within nine of these regions. Levels of gene expression were assessed in total RNA from brain tissue of 12 controls and 12 AD patients. Of all genes showing differential expression, we focused on the ornithine transcarbamylase (OTC) gene on Xp21.1., a key enzyme of the urea cycle which we found to be expressed in AD brains but not in controls, as confirmed by RT-PCR. We also detected mRNA expression of all the other urea cycle enzymes in AD brains. Immunochemistry experiments revealed that the OTC expression was strictly restricted to vascular endothelial cells in brain. Furthermore, OTC activity was 880% increased in the CSF of probable AD cases compared with controls. We analysed the association of the OTC À389 G/A and À241 A/G promoter polymorphisms with the risk of developing AD. We observed that rare haplotypes may be associated with the risk of AD through a possible modulation of the methylation of the OTC promoter. In conclusion, our results suggest the involvement of a new pathway in AD brains involving the urea cycle.

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Replication of Linkage Studies of Complex Traits: An Examination of Variation in Location Estimates

Cited by 256 publications

References 25 publications

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families

Evidence for induction of the ornithine transcarbamylase expression in Alzheimer's disease

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