Problems of reporting genetic associations with complex outcomes

Colhoun, Helen M.; McKeigue, Paul; Smith, George Davey

doi:10.1016/s0140-6736(03)12715-8

Cited by 1,088 publications

(828 citation statements)

References 48 publications

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“…Overestimation of the effect in the initial study and/or lack of power in the replication studies may be at fault. 33 The fact that the association we identified with the PRSS16 gene region was replicated in an independent family material consisting of several different nationalities, support that this finding is a true positive result. Still, ideally the initial replication should have been performed by the same analyses used in the initial dataset.…”

Section: Discussionsupporting

confidence: 70%

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

et al. 2009

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The high-risk human leukocyte antigen (HLA)-DRB1, DQA1 and DQB1 alleles cannot explain the entire type 1 diabetes (T1D) association observed within the extended major histocompatibility complex. We have earlier identified an association with D6S2223, located 2.3 Mb telomeric of HLA-A, on the DRB1*03-DQA1*0501-DQB1*0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1*0401-DQA1*03-DQB1*0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note that these associations were independent of the HLA-DRB1-DQA1-DQB1 genes, as well as of associations observed at HLA-A, -B and -C. Taken together, our results identify PRSS16 and BTN3A2, two genes thought to play important roles in regulating the immune response, as potentially novel susceptibility genes for T1D.

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Section: Discussionsupporting

confidence: 70%

Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

et al. 2009

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“…We selected 523 Han Chinese trios giving consideration to population stratification and issues of detection for power of association. 10,11 Materials and methods…”

Section: Introductionmentioning

confidence: 99%

MPZL1/PZR, a novel candidate predisposing schizophrenia in Han Chinese

Liu

Qin

et al. 2006

Mol Psychiatry

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The MPZL1/PZR gene has been mapped to 1q23.3, located in close proximity to a recognized schizophrenia susceptibility locus. Recently, the MPZL1/PZR gene has been found to be significantly upregulated in schizophrenia brain tissue and to play an important role in cell signaling, thus indicating that MPZL1/PZR could be a potential schizophrenia marker. To test this hypothesis, we selected three single nucleotide polymorphisms (SNPs) for genotyping in 523 Han Chinese trios. We found that two individual SNPs were significant at the Bonferroni's corrected significance level P < 0.017: rs3767444 (v 2 = 6.299, P = 0.0121) and rs2051656 (v 2 = 9.856, P = 0.0017). Haplotype transmission/disequilibrium tests revealed a significant association with the disease (global P-value = 1.064 Â 10 À6 ), but no specific transmission distortions. Thus, we propose that the MPZL1/PZR gene may be important in the predisposition to schizophrenia among Han Chinese.

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“…11 This may be overly pessimistic as we now appreciate that true associations with host genetic factors observed in one study may not necessarily be replicated in a second cohort. 10 It will now be interesting to see if the observations by Trachtenberg et al can be reproduced in studies examining viral adaptation and its relationships to MHC-restricted antigen recognition. The impact of individual HLA alleles can also be assessed in the context of the relevant HLA supertype in future research, with adjustment for the potential confounding factors already mentioned.…”

mentioning

confidence: 95%

“…First, the study used data from 562 individuals, however the need for even larger cohorts, consortia, or meta-analyses to achieve solid results for rare alleles and or alleles with weak effects on a phenotype is increasingly recognized. 10,11 Second, the traditional end point when investigating HIV disease has been AIDS or death. Owing to the paucity of such events in the contemporary study cohort, Trachtenberg et al were compelled to use viral set-point (the stabilization point of viral load, a characteristic of the host after the seroconversion phase and full deployment of immune response), and to estimate trajectories of CD4 cell decline as surrogate end points.…”

mentioning

confidence: 99%