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Confounding by Linkage Disequilibrium

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Confounding by Linkage Disequilibrium Journal of Human Genetics (2014) 59, 110–115 & 2014 The Japan Society of Human Genetics All rights reserved 1434-5161/14 OPEN www.nature.com/jhg CORRESPONDENCE Confounding by linkage disequilibrium Journal of Human Genetics (2014) 59, 110–115; doi:10.1038/jhg.2013.130; published online 19 December 2013 Linkage disequilibrium (LD) and confound- association between height and uterine fitted model for the test of association may ing are two widely discussed concepts in fibroids) have been reported; these associa- become overspecified, more precisely over- Genetics and in Epidemiology, yet their tions could be explained by mere LD, more adjusted because of adjustment for a covari- relationship has received only intuitive or precisely they might result from confounding ate (BMI) influenced by a genetic locus no considerations. Taken in the narrow sense, by LD or GPD between loci influencing (locus 1) in LD with the causal locus LD refers to the nonrandom association of height and uterine fibroids. (locus 2). Most importantly, the covariate alleles at two or more linked genetic loci. The needs not to be on the causal pathway, bias degree to which these alleles are associated is toward the null can still be observed if gene CONFOUNDING BY LD the basis behind genetic association studies locus 1 contributes significantly to the var- To illustrate the notion of confounding by whereby the genetic variation across target iance of the obesity trait in the study sample. LD, let us consider the simple scenario of a chromosomal intervals or over the entire Furthermore, because of the population-spe- Mendelian disease with complete or quasi- genome is captured by a set of representative cific pattern of LD, confounding by LD is complete penetrance and a typed marker at genetic markers (tagging markers). The expected to vary across populations and thus gene locus 1 in LD with an untyped causal denomination of ‘linkage’ is somehow mis- could explain failures to replicate genetic gene variant at gene locus 2. Let us further leading because LD is a special case of the association findings in comparable studies assume locus 1 affects a rare Mendelian form more general gametic phase disequilibrium (those that controlled for the same confoun- of obesity and locus 2 affects cancer but none (GPD),1 which also occurs between variants ders) in different populations. of these gene functions is known. An epide- at the mitochondrial and nuclear loci in the miological study that has collected measure- form of cytonuclear disequilibrium.2 ments of potential confounders such as body UTERINE FIBROIDS AND OBESITY Confounding occurs when an extraneous mass index (BMI) may find this trait as an One of the illustrations of this phenomenon factor, or a set of factors, can at least partially important predictor of cancer in the studied is the complex association between obesity explain an apparent association or a lack of population, whereas the positive association and uterine leiomyomas (UL, also referred to an apparent association between a risk factor may actually be explained by LD between the as fibroids). Uterine fibroids are the most and the outcome. In the former case, the typed marker and the cancer-causing allele. common tumors in women of reproductive confounding variable, or confounder, causes Thus, LD can be a source of confounding as age (about 75% of women will develop this the association to appear, whereas in the BMI predicts the cancer outcome in the condition by the time they reach menopause second case the confounder masks a real absence of an apparent causal relationship. and 25% will have symptomatic fibroids). association.3 The classical example is the Fortunately, most of the genetic determinants Cumulative exposure to estrogen is believed apparent increase of risk for heart disease of the common form of obesity identified to be a major etiological factor5 and factors with alcohol consumption, an association and replicated so far explain only small that may influence the hormonal milieu, that might in fact be due to cigarette fractions of the risk and therefore the impact such as obesity, are believed to be smoking, a covariate highly correlated with of confounding by LD on association studies associated with risk.6 However, the clearly alcohol consumption.4 of common conditions may be limited but established risk factors are age (increasing With the flood of genetic association data not negligible. By contrast, if the linked risk with increasing premenopausal age), published over the last few years, and the marker tags a gene with a sizeable effect, menopause (risk decreases with menopause) many others to come, it is the expectation for example, a major gene, then confounding and African-American ethnicity (higher risk that an increased number of the reported by LD can significantly affect the results of compared with that of non-Hispanic associations will be false findings or association studies, be they genetic or not. In Whites). Epidemiological studies have considered as such. As false finding is the our example above, if BMI is controlled for shown mixed results with respect to the common explanation for unexpected (irrele- (that is, adjusted, stratified or restricted), the association between BMI and UL. Some vant) but statistically significant associations, genetic effect of locus 2 on the cancer out- studies reported positive or no associations, in most cases these findings are not followed- come cannot be accurately estimated and the whereas other more adequately designed or up. Nevertheless, associations appealing to observed association would typically be larger studies reported an inverse J-shaped common sense (association between marital biased toward the null depending on the association,7,8 with the association reaching a status and cutaneous lymphoma) or as variance explained by locus 1 and the degree peak in the overweight category. The intriguing as they may appear (validated of LD between the two loci. In this case, the independent replication of this atypical Correspondence 111 association of BMI with UL in two cohort most significant ones peaking in the RGS7- associated with a given trait and SNPs studies of UL7,8 ruled out possible detection FH genomic interval in European Americans associated with another trait is different bias. In the absence of dose effect, plausible and in RGS7 and PLD5 (phospholipase D among cases and controls. In our example, detection bias and homogeneity of the member 5) in African Americans vanishing associations with UL at given ‘UL’ association across populations, a possible (unpublished observation). However, it is SNPs after adjustment for BMI would be an explanation for this atypical association is still not clear which of FH, RGS7, PLD5 or indication for confounding due to LD with confounding by LD, that is, the presence of a another linked gene is the actual obesity gene ‘obesity’ SNPs. A direct demonstration of this major gene for obesity in the vicinity of a UL because the association pattern across the phenomenon is suggested by the data in locus. FH-linked region varied by the UL affection Figures 2a and b, which show a differential In a recent study, we have evaluated the status and race stratum. The emerging model LD pattern at the tested ‘obesity’ and ‘UL’ role of chromosome 1q43 in the develop- is not in disagreement with our postulate SNPs in UL cases and controls, respectively. ment of UL and we have identified two of linked obesity and fibroid genes. As can be seen, SNP375 (rs4391653) in RGS7 closely linked loci influencing differentially Interestingly, the variance explained by the and SNP1320 (rs7531009) in PLD5, the two the risk of UL in European and African- candidate 1q43 obesity gene is 20–30 times SNPs that remained significantly associated American women.9 The peak of association larger (r2 ¼ 2–3%) than those reported for with BMI after controlling for the UL affec- with UL overlapped a 100 kb-long genomic typical candidate obesity genes identified in tion status, show different levels of LD with region separating two head-to-tail genes meta-analyses of genome-wide association the ‘UL’ SNPs in cases and controls. Specifi- encoding RGS7 (regulator of G-protein study.14 Nevertheless, the role of FH or the cally, the SNPs at which the association was signaling 7) and FH (tricarboxylic acid cycle linked gene in non-syndromic UL is yet to be lost after adjustment for BMI (RGS7 SNPs fumarate hydratase enzyme; Figure 1). Muta- proven. As a proof-of-concept study for the 416–418 and RGS-FH intergenic SNPs 644 tions in FH have previously been associated phenomenon of confounding by LD, we and 651) exhibit opposite levels of LD with with two rare syndromic forms of UL, analyzed the LD pattern among Chr.1q43 the two ‘obesity’ SNPs 375 and 1320 in the hereditary leiomyomatosis and renal cell single nucleotide polymorphisms (SNPs) at UL cases compared with the controls. cancer and multiple cutaneous and uterine risk for UL and/or obesity in the European Although the current data support the leiomyomatosis.10,11 The current paradigm group of the National Institute of presence of colocalized susceptibility loci for associates FH to a tumor suppressor gene10– Environmental Health Sciences Uterine obesity13,15,16 and reproduction-related 12 but several observations argue against it Fibroid Study. Table 1 shows the list of traits,9–11,17,18 it remains to be seen whether and models for an alternative 1q43 fibroid 1q43 SNPs of interest, their relative position the present proof-of-concept study will be gene linked to FH and/or a pleiotropic FH and the significance of their association with strengthen or weakened following gene have been postulated.9 the UL and the BMI outcomes. To assess the identification and mutational analyses.
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