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Significance of the Hardy–Weinberg equilibrium in genetic association studies
Psychiatry Research 190 (2011) 165
Contents lists available at ScienceDirect
Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s
Letter to the Editor Significance of the Hardy–Weinberg equilibrium in genetic association studies
To the Editor: I read the interesting study which was reported by Yun et al. (2011) on the association between genetic polymorphism (rs27388) of multiple epidermal growth factor-like domains 10 (MEGF10, MIM: 612453) and susceptibility to schizophrenia in a Chinese case–control sample. The authors found that there was no association between rs27388 polymorphism of MEGF10 and schizophrenia. Also, they mentioned that their finding is not consistent with a previous report by Chen et al. (2008). Based on several meta-analyses, there are different types of associations between genetic polymorphisms (Hung et al., 2005) and at least some multifactorial traits among various ethnic groups (Saadat, 2006; Saadat and Ansari-Lari, 2009). For example, polymorphism of GSTT1 associated with risk of gastric cancer only among Caucasians (Saadat, 2006). Therefore, the different genetic backgrounds of populations in the studies by Yun et al. (2011) and Chen et al. (2008) (Asian and Caucasian, respectively) may be a responsible factor. However, I suggest that this point (differences in gene pools) may not be valid for the interpretation of the difference between these two studies. The “STrengthening the REporting of Genetic Association” studies statement strongly recommended that authors of genetic association studies state whether Hardy–Weinberg equilibrium was considered (Little et al., 2009). Yun et al. (2011) in their Letter to the Editor mentioned that there was no significant difference between observed and expected frequencies of the genotypes based on Hardy–Weinberg equilibrium. However, based on the data presented in Table 1 of Yun et al. (2011), there were statistically significant deviations from the HWE (for the control group: χ2 = 22.38, df = 1, P b 0.0001; for the case group: χ2 = 24.07, df = 1, P b 0.0001). There was an excess of heterozygotes in the controls and patients. Unfortunately, the authors not only did not mention this point, but also mentioned that genotypic distributions were in Hardy–Weinberg equilibrium. We know that in a very large population with random mating, the allelic frequencies will remain stable from generation to generation provided that there is no mutation, migration, or natural selection. In the presence of evolutionary pressure, or nonrandom mating, statistically significant deviation from Hardy–Weinberg equilibrium might be observed. On the other hand, if there was any problem in the
DOI of original article: 10.1016/j.psychres.2010.08.002 0165-1781/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2011.01.022
genotyping determination, we could observe deviation from Hardy– Weinberg equilibrium the expected frequencies according to Hardy– Weinberg equilibrium. It is possible that the control group showed significant deviation from Hardy–Weinberg equilibrium as follows: 1) There was a kind of artifact occurring during determination of genotypes. 2) Controls were selected from different gene pools. 3) There was strong linkage disequilibrium between the polymorphism of rs27388 and other polymorphisms such that they were not naturally neutral. Finally, it should be noted that the results of Yun et al. (2011) should be interpreted with caution. Acknowledgement This study was supported by Shiraz University.
References Chen, X., Wang, X., Chen, Q., Williamson, V., van den Oord, E., Maher, B.S., O'Neill, F.A., Walsh, D., Kendler, K.S., 2008. MEGF10 association with schizophrenia. Biological Psychiatry 63, 441–448. Hung, R.J., Hall, J., Bernnan, P., Boffestta, P., 2005. Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review. American Journal of Epidemiology 162, 925–942. Little, J., Higgins, J.P., Ioannidis, J.P., Moher, D., Gagnon, F., von Elm, E., Khoury, M.J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R.E., Zou, G.Y., Hutchings, K., Johnson, C.Y., Tait, V., Wiens, M., Golding, J., van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A., Birkett, N., 2009. STrengthening the REporting of Genetic Association studies (STREGA)—an extension of the STROBE statement. European Journal of Clinical Investigation 39, 247–266. Saadat, M., 2006. Genetic polymorphisms of glutathione S-transferase T1 (GSTT1) and susceptibility to gastric cancer: a meta-analysis. Cancer Science 97, 505–509. Saadat, M., Ansari-Lari, M., 2009. Polymorphism of XRCC1 (at codon 399) and susceptibility to breast cancer: a meta-analysis of the literatures. Breast Cancer Research and Treatment 115, 137–144. Yun, L., Gu, Y., Hou, Y., 2011. No association between schizophrenia and rs27388 of the MEGF10 gene in Chinese case–control sample. Psychiatry Research 186 (2-3), 467–468.
Mostafa Saadat Department of Biology, College of Sciences, Shiraz University, Shiraz 71454, Iran E-mail address: [email protected] 29 September 2010
Contents lists available at ScienceDirect
Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s
Letter to the Editor Significance of the Hardy–Weinberg equilibrium in genetic association studies
To the Editor: I read the interesting study which was reported by Yun et al. (2011) on the association between genetic polymorphism (rs27388) of multiple epidermal growth factor-like domains 10 (MEGF10, MIM: 612453) and susceptibility to schizophrenia in a Chinese case–control sample. The authors found that there was no association between rs27388 polymorphism of MEGF10 and schizophrenia. Also, they mentioned that their finding is not consistent with a previous report by Chen et al. (2008). Based on several meta-analyses, there are different types of associations between genetic polymorphisms (Hung et al., 2005) and at least some multifactorial traits among various ethnic groups (Saadat, 2006; Saadat and Ansari-Lari, 2009). For example, polymorphism of GSTT1 associated with risk of gastric cancer only among Caucasians (Saadat, 2006). Therefore, the different genetic backgrounds of populations in the studies by Yun et al. (2011) and Chen et al. (2008) (Asian and Caucasian, respectively) may be a responsible factor. However, I suggest that this point (differences in gene pools) may not be valid for the interpretation of the difference between these two studies. The “STrengthening the REporting of Genetic Association” studies statement strongly recommended that authors of genetic association studies state whether Hardy–Weinberg equilibrium was considered (Little et al., 2009). Yun et al. (2011) in their Letter to the Editor mentioned that there was no significant difference between observed and expected frequencies of the genotypes based on Hardy–Weinberg equilibrium. However, based on the data presented in Table 1 of Yun et al. (2011), there were statistically significant deviations from the HWE (for the control group: χ2 = 22.38, df = 1, P b 0.0001; for the case group: χ2 = 24.07, df = 1, P b 0.0001). There was an excess of heterozygotes in the controls and patients. Unfortunately, the authors not only did not mention this point, but also mentioned that genotypic distributions were in Hardy–Weinberg equilibrium. We know that in a very large population with random mating, the allelic frequencies will remain stable from generation to generation provided that there is no mutation, migration, or natural selection. In the presence of evolutionary pressure, or nonrandom mating, statistically significant deviation from Hardy–Weinberg equilibrium might be observed. On the other hand, if there was any problem in the
DOI of original article: 10.1016/j.psychres.2010.08.002 0165-1781/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2011.01.022
genotyping determination, we could observe deviation from Hardy– Weinberg equilibrium the expected frequencies according to Hardy– Weinberg equilibrium. It is possible that the control group showed significant deviation from Hardy–Weinberg equilibrium as follows: 1) There was a kind of artifact occurring during determination of genotypes. 2) Controls were selected from different gene pools. 3) There was strong linkage disequilibrium between the polymorphism of rs27388 and other polymorphisms such that they were not naturally neutral. Finally, it should be noted that the results of Yun et al. (2011) should be interpreted with caution. Acknowledgement This study was supported by Shiraz University.
References Chen, X., Wang, X., Chen, Q., Williamson, V., van den Oord, E., Maher, B.S., O'Neill, F.A., Walsh, D., Kendler, K.S., 2008. MEGF10 association with schizophrenia. Biological Psychiatry 63, 441–448. Hung, R.J., Hall, J., Bernnan, P., Boffestta, P., 2005. Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review. American Journal of Epidemiology 162, 925–942. Little, J., Higgins, J.P., Ioannidis, J.P., Moher, D., Gagnon, F., von Elm, E., Khoury, M.J., Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R.E., Zou, G.Y., Hutchings, K., Johnson, C.Y., Tait, V., Wiens, M., Golding, J., van Duijn, C., McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King, R., Infante-Rivard, C., Stewart, A., Birkett, N., 2009. STrengthening the REporting of Genetic Association studies (STREGA)—an extension of the STROBE statement. European Journal of Clinical Investigation 39, 247–266. Saadat, M., 2006. Genetic polymorphisms of glutathione S-transferase T1 (GSTT1) and susceptibility to gastric cancer: a meta-analysis. Cancer Science 97, 505–509. Saadat, M., Ansari-Lari, M., 2009. Polymorphism of XRCC1 (at codon 399) and susceptibility to breast cancer: a meta-analysis of the literatures. Breast Cancer Research and Treatment 115, 137–144. Yun, L., Gu, Y., Hou, Y., 2011. No association between schizophrenia and rs27388 of the MEGF10 gene in Chinese case–control sample. Psychiatry Research 186 (2-3), 467–468.
Mostafa Saadat Department of Biology, College of Sciences, Shiraz University, Shiraz 71454, Iran E-mail address: [email protected] 29 September 2010