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No gene is an island: the flip-flop phenomenon - PubMed

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No gene is an island: the flip-flop phenomenon

Ping-I Lin et al. Am J Hum Genet. 2007 Mar.

Erratum in

Am J Hum Genet. 2007 May;80(5):1002

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.

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Figures

**Figure 1.**
Penetrance values for each two-locus genotype combination under different models of multilocus effect. The penetrance values were calculated by specifying
α=.001
,
θ₁=0.1
, and
θ₂=0.2
for each model.

**Figure 2.**
ORs corresponding to the effect size of allele A under models I and IV. Parameters for each situation are specified. A,
f=0.001
,
θ₁=0.1
, and
θ₂=0.2
under model I. B,
f=0.001
,
θ₁=0.1
, and
θ₂=-0.2
under model I. C,
f=0.001
,
θ₁=0.1
, and
θ₂=0.2
under model IV. D,
f=0.001
,
θ₁=0.1
, and
θ₂=-0.2
under model IV.

**Figure 3.**
Directions of allelic association for the A allele in different situations. We used the statistic
χ=(P_A-P_B)/
, where
P=(P_A+P_B)/2
, to demonstrate how the direction of allelic association varies depending on θ₂, given the same frequency of the A (and B) allele (∼50%) and model of multilocus effect. θ₁ is fixed at 0.1 for all models. Panel A indicates the situation where A is a risk allele and B is also a risk allele; panel B indicates the situation where the A allele is a risk allele and the B allele is a protective allele.

formula image — **Figure 3.**
Directions of allelic association for the A allele in different situations. We used the statistic
χ=(P_A-P_B)/
, where
P=(P_A+P_B)/2
, to demonstrate how the direction of allelic association varies depending on θ₂, given the same frequency of the A (and B) allele (∼50%) and model of multilocus effect. θ₁ is fixed at 0.1 for all models. Panel A indicates the situation where A is a risk allele and B is also a risk allele; panel B indicates the situation where the A allele is a risk allele and the B allele is a protective allele.

**Figure 4.**
The effect of the Val allele (i.e., the A allele at *Nla*III RSP) on SCZD across 32 populations. Allelic effect is presented by OR. For model A,
θ₁=0.1
and
θ₂=0.2
; for model B,
θ₁=0.1
and
θ₂=0.4
; for model C,
θ₁=0.1
and
θ₂=0.8
. For all four models,
f=0.001
.

**Figure 5.**
The effect of the Val allele (presented by OR) on SCZD in the Cambodian population, given different disease models (i.e., different effect ratios for the P2 promoter compared with the Val allele).

Comment in

Genetic flip-flop without an accompanying change in linkage disequilibrium.
Zaykin DV, Shibata K. Zaykin DV, et al. Am J Hum Genet. 2008 Mar;82(3):794-6; author reply 796-7. doi: 10.1016/j.ajhg.2008.02.001. Am J Hum Genet. 2008. PMID: 18319078 Free PMC article. No abstract available.

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References

Web Resource

1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for autistic disorder, GSTO1, AD, COMT, SCZD, and GAPDH)

References

1. Devlin B, Cook EH Jr, Coon H, Dawson G, Grigorenko EL, McMahon W, Minshew N, Pauls D, Smith M, Spence MA, et al (2005) Autism and the serotonin transporter: the long and short of it. Mol Psychiatry 10:1110–111610.1038/sj.mp.4001724 - DOI - PubMed
1. Betancur C, Corbex M, Spielewoy C, Philippe A, Laplanche JL, Launay JM, Gillberg C, Mouren-Simeoni MC, Hamon M, Giros B, et al (2002) Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder. Mol Psychiatry 7:67–71 - PMC - PubMed
1. Maestrini E, Lai C, Marlow A, Matthews N, Wallace S, Bailey A, Cook EH, Weeks DE, Monaco AP, The International Molecular Genetic Study of Autism Consortium (1999) Serotonin transporter (5-HTT) and γ-aminobutyric acid receptor subunit β3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. Am J Med Genet 88:492–49610.1002/(SICI)1096-8628(19991015)88:5<492::AID-AJMG11>3.0.CO;2-X - DOI - PubMed
1. McCauley JL, Olson LM, Dowd M, Amin T, Steele A, Blakely RD, Folstein SE, Haines JL, Sutcliffe JS (2004) Linkage and association analysis at the serotonin transporter (SLC6A4) locus in a rigid-compulsive subset of autism. Am J Med Genet B Neuropsychiatr Genet 127:104–11210.1002/ajmg.b.20151 - DOI - PubMed
1. Tordjman S, Gutknecht L, Carlier M, Spitz E, Antoine C, Slama F, Carsalade V, Cohen DJ, Ferrari P, Roubertoux PL, et al (2001) Role of the serotonin transporter gene in the behavioral expression of autism. Mol Psychiatry 6:434–43910.1038/sj.mp.4000873 - DOI - PubMed

No gene is an island: the flip-flop phenomenon - PubMed