Caught in the trio trap? Potential selection bias inherent to association studies usings parent‐offspring trios

Schulze, Thomas G.; Müller, Daniel J.; Krauss, Herbert H.; Groß, Magdalena; Bauer, Irina; Fangerau-Lefèvre, Heiner; Illes, Franciska; Ohlraun, Stephanie; Fimmers, Rolf; Cichon, Sven; Held, Tilo; Propping, Peter; Nöthen, Markus M.; Maier, Wolfgang; Rietschel, Marcella

doi:10.1002/ajmg.1348

Cited by 21 publications

(19 citation statements)

References 18 publications

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“…Family-based association strategies, i.e., the Transmission Disequilibrium Test (TDT) [Spielman et al, 1993;Ewans and Spielman, 1995] and the Haplotype Relative Risk (HRR) [Falk and Rubinstein, 1987] designs are preferred. However, also TDT and HRR designs have been discussed as having some limitations [Schulze et al, 2001].…”

Section: Discussionmentioning

confidence: 99%

MCP‐1 gene (SCYA2) and schizophrenia: A case‐control association study

Mundo

Altamura

Vismara

et al. 2004

American J of Med Genetics Pt B

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Dysregulation of the inflammatory response system has been linked to the pathophysiology of schizophrenia. Abnormal levels of proinflammatory cytokines and their receptors have been found in peripheral blood and cerebrospinal fluid of schizophrenic patients, suggesting the presence of immune activation. Monocyte chemoattractant protein 1 (MCP-1) influences the expression of cytokines related to T helper responses. MCP-1 also exerts several effects on monocytes, including the expression of several proinflammatory genes. The A-2518G polymorphism of the MCP-1 gene (SCYA2) appears to affect the transcriptional activity and monocyte MCP-1 production. The aim of this case-control study was to investigate the potential role of SCYA2 (A-2518G polymorphism) in conferring susceptibility to schizophrenia and to the resistance to antipsychotic treatment. The sample studied consisted of 191 DSM-IV schizophrenia or schizoaffective disorder (depressive subtype) patients and 161 matched healthy controls. No significant genotypic (chi(2) = 0.278, df = 2, P = 0.986) or allelic (chi(2) = 0.021, df = 1, P = 0.884) association was found between the A-2518G variant of the SCYA2 and the diagnosis. No differences in the age at onset of schizophrenia were found between the three genotype groups identified. Significant genotypic association was found between the A-2518G variant of the SCYA2 and the resistance to antipsychotic treatment (chi(2) = 6.26, df = 2, P = 0.04), with resistant patients more frequently carrying the G allele. The odds ratio associated to the presence of the G allele was 2.39 (95% CI = 1.14-4.98). These data suggest that the A-2518G variant of the SCYA2 has not a major role in the pathogenesis of schizophrenia, while it could be implicated in the resistance to antipsychotic treatment.

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Section: Discussionmentioning

confidence: 99%

MCP‐1 gene (SCYA2) and schizophrenia: A case‐control association study

Mundo

Altamura

Vismara

et al. 2004

American J of Med Genetics Pt B

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“…Although the specific reason(s) for the discrepancies between the two study designs with respect to this region are uncertain, several factors may have contributed to the discordant findings. First, selection of healthy controls (or unaffected members in the family study) and clinical heterogeneity of the BD patient group in both designs may be factors that underlie inconsistency in replication or confirmation for those three SNPs of the gene: phenotypic heterogeneity such as reflected by AAO, for example, is well recognized as a factor that can contribute to discordant findings between family and case‐control designs (38, 39). Second, because of the challenges to recruitment that result in smaller datasets than can be obtained in case‐control studies, family study designs are relatively underpowered to detect genetic effects of modest or small magnitude (40).…”

Section: Discussionmentioning

confidence: 99%

TRPM2 variants and bipolar disorder risk: confirmation in a family‐based association study

Chun

Cooke

et al. 2009

Bipolar Disorders

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Original ArticleTRPM2 variants and bipolar disorder risk: confirmation in a family-based association studyAlthough genome scan studies of bipolar disorder (BD) have illuminated several chromosomal loci which satisfy consensus criteria as harboring genes involved in BD (1, 2), evidence is sparse regarding specific genes within these regions that contribute to this complex trait. Guided by observations implicating altered intracellular calcium (Ca 2+ ) signaling dynamics in the pathophysiology of BD (3), we focused on a priority candidate, the nonselective cation permeable transient receptor potential melastatin type 2 (TRPM2) channel, based on its involvement in processes regulating Objective: Recent case-control studies implicate the transient receptor potential melastatin 2 (TRPM2) channel in conferring risk for bipolar disorder (BD), though the risk variants differed. As confounding effects of population structure could not be unequivocally ruled out as the basis for the discordance, we tested the association of TRPM2 with BD in a family design, which is immune to population stratification, for those TRPM2 single nucleotide polymorphisms (SNPs) previously reported as associated with BD. Methods:The exon 11 SNP (rs1556314) and four informative intronic SNPs (rs1785437, rs1618355, rs933151, and rs749909) were genotyped in 300 BD families by TaqMan allelic discrimination and results were analyzed using v 2 test, transmission disequilibrium test, and pedigreebased association. SNP rs1556314 was also genotyped in our casecontrol sample set comprised of 184 BD and 195 healthy Caucasian subjects.Results: The SNP rs1556314 in exon 11 was significantly associated with bipolar disorder type I (BD-I) (p = 0.011, p permutation = 0.015) in the case-control dataset and in the family design (p = 0.018, p permutation = 0.052, TDTPHASE). Interestingly, the C-T-A haplotype of SNPs rs1618355, rs933151, and rs749909 was significantly associated with early age at onset in BD-I families.Conclusion: Significant association of TRPM2 genetic variants with BD in case-control and family datasets further supports a role for TRPM2 in the pathogenesis of this disorder. Overtransmission of the G allele of rs1556314 at exon 11 of TRPM2 in BD-I but not bipolar disorder type II (BD-II) further supports different genetic contributions to the pathogenesis of these bipolar phenotypes.

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“…Firstly, the overwhelming number of positive associations carried out in psychiatric genetics, including many of the findings mentioned in this review, are likely going to end up as false positives (type I error), usually due to population stratification or chance associations from multiple testing [146]. This is a common problem of all case control studies; in the attempt to circumvent this bias, family based association studies have been proposed [147], but, apart from recruiting difficulties, those studies are not without criticisms too [148].…”

Section: Methodological Problemsmentioning

confidence: 99%

Personality and Genetics

Serretti¹,

Calati²,

Ferrari³

et al. 2007

CPSR

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In the last few years the correlation between personality and genetics has been largely investigated. Harm Avoidance seems to be strongly associated with the serotonin transporter gene. The 5-HT1A and the 5-HT3A serotonin receptors and the D2 and D4 dopamine receptors, seem to be also involved, even if results are less unequivocal. Novelty Seeking seems to be associated with dopamine D4 receptor gene, but also the D2 and D3 dopamine receptors, the 5-HT2A serotonin receptor, the MAO-A and the COMT genes have been hypothesized as involved in this trait. Studies on Reward Dependence, Persistence, Self-Directedness, Cooperativeness and SelfTranscendence dimensions are still conflicting. Though further studies are necessary to replicate and validate those results, genetic factors play an important role for specific susceptibilities of human personality.

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Caught in the trio trap? Potential selection bias inherent to association studies usings parent‐offspring trios

Cited by 21 publications

References 18 publications

MCP‐1 gene (SCYA2) and schizophrenia: A case‐control association study

MCP‐1 gene (SCYA2) and schizophrenia: A case‐control association study

TRPM2 variants and bipolar disorder risk: confirmation in a family‐based association study

Personality and Genetics

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