No Gene Is an Island: The Flip-Flop Phenomenon
The American Journal of Human GeneticsPublished 5 February 2007Open access
Ping‐I Lin, Jeffery M. Vance, Margaret A. Pericak‐Vance, Eden R. Martin
Citations468
SJR quartileQ1
SJR score4.53
SNIP2.47
Generate an AI Snapshot to get a quick, structured summary of this paper.
Study Snapshot
ObjectiveStudy objective
MethodsResearch methodology
PopulationPopulation studied
Sample sizeSample sizes
OutcomesStudy outcomes here
ResultsStudy results comes here
LimitationsResearch study limitations comes here
A concise AI-generated summary of the paper will appear here once you click Generate AI Snapshot.
TL;DR
T theoretical modeling is used to demonstrate that flip-flop associations can occur when the investigated variant is correlated, through interactive effects or linkage disequilibrium, with a causal variant at another locus, and it is shown how these findings could explain previous reports of flip-Flop associations.
Abstract
An increasing number of publications are replicating a previously reported disease-marker association but with the risk allele reversed from the previous report. Do such "flip-flop" associations confirm or refute the previous association findings? We hypothesized that these associations may indeed be confirmations but that multilocus effects and variation in interlocus correlations contribute to this flip-flop phenomenon. We used theoretical modeling to demonstrate that flip-flop associations can occur when the investigated variant is correlated, through interactive effects or linkage disequilibrium, with a causal variant at another locus, and we show how these findings could explain previous reports of flip-flop associations.
Keywords
MedicineNeuroscienceBiochemistry, Genetics and Molecular Biology
Scienceα-Synuclein Locus Triplication Causes Parkinson's Disease
4,407 Citations2003A. B. Singleton, Andrew Singleton +22 more
NeurologyAssociation of apolipoprotein E allele ϵ4 with late‐onset familial and sporadic Alzheimer's disease
3,780 Citations1993Ann M. Saunders, Warren J. Strittmatter +12 more
Data support the involvement of ApoE epsilon 4 in the pathogenesis of late-onset familial and sporadic AD and suggest it may operate as a susceptibility gene (risk factor) for the clinical expression of AD.
The LancetProblems of reporting genetic associations with complex outcomes
1,203 Citations2003Helen M. Colhoun, Paul McKeigue +1 more
Nature GeneticsGenome-wide strategies for detecting multiple loci that influence complex diseases
904 Citations2005Jonathan Marchini, Peter Donnelly +1 more
Analytical methods that explicitly look for statistical interactions between loci are shown to be computationally feasible, even for studies of hundreds of thousands of loci, and to be more powerful than traditional analyses under a range of models for interlocus interactions.
American Journal of PsychiatryAssociation Between a Functional Catechol <i>O</i>-Methyltransferase Gene Polymorphism and Schizophrenia: Meta-Analysis of Case-Control and Family-Based Studies
345 Citations2003Stephen J. Glatt, Stephen V. Faraone +1 more
The authors suggest that case-control studies should use methods of genomic control to avoid being confounded by population stratification and call for more family-based studies to confirm the association between COMT and schizophrenia in European samples and to clarify its contribution to risk in Asian samples.
Biological PsychiatryCatechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: A large-scale association study plus meta-analysis
260 Citations2004Jinbo Fan, Chang-Shun Zhang +7 more
The data provide minimal evidence that the Val allele is a susceptibility factor for schizophrenia in either European or Asian populations.
Human Molecular GeneticsGlutathione S-transferase omega-1 modifiesage-at-onset of Alzheimer disease and Parkinson disease
235 Citations2003Yi‐Ju Li
Genetic linkage of loci controlling age-at-onset in Alzheimer disease and Parkinson's disease to a 15 cM region on chromosome 10q was reported and the process of 'genomic convergence' was applied to prioritize and reduce the number of candidate genes for further analysis.
Molecular PsychiatryRole of the serotonin transporter gene in the behavioral expression of autism
192 Citations2001Sylvie Tordjman, Lise Gutknecht +9 more
The data indicate that HTT promoter alleles by themselves do not convey risk for autism, but, rather, modify the severity of autistic behaviors in the social and communication domains, and suggest that future research on the genetics of autism should carefully assess each of the major behavioral domains.
Molecular PsychiatryAutism and the serotonin transporter: the long and short of it
187 Citations2005Bernie Devlin, Edwin H. Cook +12 more
Determining the factors influencing the relationship between autism phenotypes and HTTLPR variation, as well as other loci in SLC6A4, could be an important advance in the authors' understanding of this complex disorder.
American Journal of Medical GeneticsEvidence for an association with the serotonin transporter promoter region polymorphism and autism
165 Citations2001Nurit Yirmiya, Tammy Pilowsky +5 more
Examination of functional polymorphisms in a small family-based design toward identifying candidate genes that confer risk for autism found an excess of the long/long 5-HTTLPR genotype, which could provide a partial molecular explanation for high platelet serotonin content in autism.
GeneticsReconstituting the Frequency Spectrum of Ascertained Single-Nucleotide Polymorphism Data
164 Citations2004Rasmus Nielsen, Melissa J. Hubisz +1 more
This work shows how the problem of allele frequency distributions that are biased by the ascertainment protocol can be corrected by obtaining maximum-likelihood estimates of the true allele frequency distribution.
American Journal of Medical GeneticsSerotonin transporter (5-HTT) and ?-aminobutyric acid receptor subunit ?3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families
160 Citations1999Elena Maestrini, Cecilia Lai +7 more
No significant evidence of association or linkage was found at any of the markers tested, indicating that the 5-HTT and the GABRB3 genes are unlikely to play a major role in the aetiology of autism in the family data set.
Proceedings of the National Academy of SciencesAssociation of late-onset Alzheimer's disease with genetic variation in multiple members of the <i>GAPD</i> gene family
137 Citations2004Yonghong Li, Petra Nowotny +30 more
A large-scale single-nucleotide polymorphism (SNP)-based association study across the region of linkage on chromosome 12 in multiple case-control series raises the possibility that GAPD genes are AD risk factors, a hypothesis that is consistent with the role of GAPD in neuronal apoptosis.
American Journal of Medical Genetics Part B Neuropsychiatric GeneticsLinkage and association analysis at the serotonin transporter (<i>SLC6A4</i>) locus in a rigid‐compulsive subset of autism
134 Citations2003Jacob L. McCauley, Lana M. Olson +7 more
Data indicate that a common allele within the coding region of SLC6A4 is not responsible for the observed linkage, however, the presence of heterogeneous disease variants within the block or the existence of a common disease‐associated allele either upstream or downstream of this block is possible.
Molecular PsychiatryVariants in the catechol-o-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families
127 Citations2004X Chen, X Wang +3 more
The study of association of COMT with schizophrenia in Irish families with a high density of schizophrenia concluded that COMT gene is associated with schizophrenia and carries a small but significant risk to the susceptibility in the Irish subjects.
Molecular PsychiatrySerotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder
123 Citations2002Catalina Betancur, Marilys Corbex +10 more
NeurologyPolymorphisms in glutathione <i>S</i> -transferase omega-1 and AD, vascular dementia, and stroke
100 Citations2004Heike Kölsch, Michael Linnebank +11 more
The GSTO1 Asp allele may be a genetic risk factor for cerebrovascular diseases, and might influence the course of Alzheimer disease, even though effects vary in different studies.
Pharmacogenetics and GenomicsCYP2D6 polymorphisms and the risk of tardive dyskinesia in schizophrenia: a meta-analysis
99 Citations2005Nikolaos A. Patsopoulos, Evangelia Ntzani +2 more
CYP2D6 loss of function alleles may predispose to tardive dyskinesia in patients with schizophrenia under treatment, but bias cannot be excluded.
Molecular PsychiatrySerotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder
88 Citations2002Catalina Betancur, Marilys Corbex +10 more
The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs, and the results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism.
Molecular PsychiatryHaplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia
76 Citations2004Alan R. Sanders, Ioana Rusu +7 more
Previous association signals of schizophrenia to COMT markers are supported, and it is suggested that ARVCF might contribute to this signal.
American Journal of Medical Genetics Part B Neuropsychiatric GeneticsAssociation between Val<sup>108/158</sup>met polymorphism of the<i>COMT</i>gene and schizophrenia
76 Citations2003Ikwunga Wonodi, O. Colin Stine +3 more
Calculation of the population attributable risk suggests that the Val allele accounts for as much as 23% of schizophrenia in this population (range: 3–38%) and provides support for a role of this variant in the etiopathophysiology of schizophrenia.
Molecular PsychiatryCOMT haplotypes suggest P2 promoter region relevance for schizophrenia
73 Citations2004Meg A. Palmatier, A.J. Pakstis +16 more
New haplotype data support the hypothesis of a relevant cis variant linked to the rs737865 site, possibly just upstream in the P2 promoter driving transcription of the predominant form of COMT in the brain.
Neuroscience LettersAlpha synuclein promoter and risk of Parkinson's disease: microsatellite and allelic size variability
65 Citations2002Eng‐King Tan, Christopher Tan +7 more
Variability of the microsatellite region and potential interacting factors that could affect alpha synuclein gene transcription should be further examined.
Mechanisms of Ageing and DevelopmentDNA variability of human genes
52 Citations2003Julie A. Schneider, Manish Pungliya +5 more
A deeper understanding of how SNPs are distributed within human genes and the patterns of linkage disequilibrium among SNPs will be of vital importance when trying to identify the genetic contribution to complex phenotypes such as aging.
European NeuropsychopharmacologyFunctional catechol-O-methyltransferase gene polymorphism and susceptibility to schizophrenia
41 Citations2002Tae‐Won Park
A significant combined effect was seen: the cases with concurrent family history of schizophrenia and the COMT-L allele containing genotypes had an almost 4-fold (OR=3.9, 95% CI=1.1-14.3) higher risk of schizophrenia compared to controls with theCOMT-HH genotypes.
American Journal of Medical GeneticsLinkage of chromosome 13q32 to schizophrenia in a large veterans affairs cooperative study sample
31 Citations2002Stephen V. Faraone, Andrew D. Skol +17 more
Several prior reports have suggested that chromosomal region 13q32 may harbor a schizophrenia susceptibility gene, and linkage between chromosome 13 markers and schizophrenia in 166 families, each with two or more affected members, was assessed.
NeurologyExploring the association of glyceraldehyde-3-phosphate dehydrogenase gene and Alzheimer disease
25 Citations2006Ping‐I Lin, Eden R. Martin +8 more
The GAPD gene and its pseudogene may play a role in the development of late-onset Alzheimer disease, however, the effect, if any, is likely to be limited.
PhysiologyUse of Recombinant Congenic Strains in Mapping Disease-Modifying Genes
8 Citations2004Jana Müllerová, Pavel Hozák
Recombinant congenic strains of mice are reported on, a powerful tool for genetic dissection of a complex trait and genes involved in complex disease remain largely unknown.