No Gene Is an Island: The Flip-Flop Phenomenon

Center for Human Genetics, Duke University Medical Center, Durham, NC, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 04/2007; 80(3):531-8. DOI: 10.1086/512133
Source: PubMed


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.

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    • "homozygous A-carriers vs. GA and GG genotype ). Finally, the so-called flip flop, the phenomena by which both alleles in a biallelic SNP show association as a result of linkage to a nearby, causal polymorphism, might also explain apparently inconsistent findings(Lin et al., 2007). One strength of our study is that we have investigated several SNPs across the LEP and LEPR genes, most of which have not been analyzed for AIWG yet. "
    Society of Biological Psychiatry; 05/2015
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    • "However, we consider the finding genuine, and attribute it to the well-known phenomenon where by different alleles of the same variant are associated with the same phenotype. This phenomenon was first described in 2007 (Lin et al, 2007), and has been observed for some of the most robust genetic association findings in both humans (Lin et al, 2007; Maher et al, 2010), and Drosophila (Gruber et al, 2007). These authors proposed that this phenomenon may be explained by an interaction or correlation between the examined (proxy) variant and an unknown causal variant. "
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    ABSTRACT: Genetic factors play as large a role as environmental factors in the etiology of alcohol dependence. Although genome-wide association studies (GWAS) enable systematic searches for loci not hitherto implicated in the etiology of alcohol dependence, many true findings may be missed due to correction for multiple testing. The aim of the present study was to circumvent this limitation by searching for biological system-level differences, and then following up these findings in humans and animals. Gene-set based analysis of GWAS data from 1333 cases and 2168 controls identified 19 significantly associated gene-sets of which five could be replicated in an independent sample. Clustered in these gene-sets were novel and previously identified susceptibility genes. The most frequently present gene, ie in 6 out of 19 gene-sets, was X-ray repair complementing defective repair in Chinese hamster cells 5 (XRCC5). Previous human and animal studies have implicated XRCC5 in alcohol sensitivity. This phenotype is inversely correlated with the development of alcohol dependence, presumably since more alcohol is required to achieve the desired effects. In the present study, the functional role of XRCC5 in alcohol dependence was further validated in animals and humans. Drosophila mutants with reduced function of Ku80-the homolog of mammalian XRCC5-due to RNAi silencing showed reduced sensitivity to ethanol. In humans with free access to intravenous ethanol self-administration in the laboratory, the maximum achieved blood alcohol concentration was influenced in an allele-dose dependent manner by genetic variation in XRCC5. In conclusion, our convergent approach identified new candidates and generated independent evidence for the involvement of XRCC5 in alcohol dependence.Neuropsychopharmacology accepted article preview online, 18 July 2014; doi:10.1038/npp.2014.178.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2014; 40(2). DOI:10.1038/npp.2014.178 · 7.05 Impact Factor
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    • "However, there was some evidence of increased risk of mild malaria in Dogon with the 202A mutation, but it only attained borderline statistical significance in females. It is possible that this result could be explained by the presence of a flip-flop mutation [31] or allelic heterogeneity [8]. The rs915942 polymorphism (and others in LD) was found to be associated with asymptomatic malaria in Dogon females. "
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    ABSTRACT: Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with protection from severe malaria, and potentially uncomplicated malaria phenotypes. It has been documented that G6PD deficiency in sub-Saharan Africa is due to the 202A/376G G6PD A-allele, and association studies have used genotyping as a convenient technique for epidemiological studies. However, recent studies have shown discrepancies in G6PD202/376 associations with severe malaria. There is evidence to suggest that other G6PD deficiency alleles may be common in some regions of West Africa, and that allelic heterogeneity could explain these discrepancies. Methods A cross-sectional epidemiological study of malaria susceptibility was conducted during 2006 and 2007 in the Sahel meso-endemic malaria zone of Mali. The study included Dogon (n = 375) and Fulani (n = 337) sympatric ethnic groups, where the latter group is characterized by lower susceptibility to Plasmodium falciparum malaria. Fifty-three G6PD polymorphisms, including 202/376, were genotyped across the 712 samples. Evidence of association of these G6PD polymorphisms and mild malaria was assessed in both ethnic groups using genotypic and haplotypic statistical tests. Results It was confirmed that the Fulani are less susceptible to malaria, and the 202A mutation is rare in this group (< 1% versus Dogon 7.9%). The Betica-Selma 968C/376G (~11% enzymatic activity) was more common in Fulani (6.1% vs Dogon 0.0%). There are differences in haplotype frequencies between Dogon and Fulani, and association analysis did not reveal strong evidence of protective G6PD genetic effects against uncomplicated malaria in both ethnic groups and gender. However, there was some evidence of increased risk of mild malaria in Dogon with the 202A mutation, attaining borderline statistical significance in females. The rs915942 polymorphism was found to be associated with asymptomatic malaria in Dogon females, and the rs61042368 polymorphism was associated with clinical malaria in Fulani males. Conclusions The results highlight the need to consider markers in addition to G6PD202 in studies of deficiency. Further, large genetic epidemiological studies of multi-ethnic groups in West Africa across a spectrum of malaria severity phenotypes are required to establish who receives protection from G6PD deficiency.
    Malaria Journal 07/2014; 13(1):270. DOI:10.1186/1475-2875-13-270 · 3.11 Impact Factor
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