Retraction and Correction RETRACTION GENETICS, SOCIAL SCIENCES Retraction for ‘‘PKNOX2 gene is significantly associated with substance dependence in European-origin women,’’ by Xiang Chen, Kelly Cho, Burton H. Singer, and Heping Zhang, which published online August 31, 2009, in Proc Natl Acad Sci USA (10.1073/pnas.0908521106). The authors wish to retract this paper because its publication violates the Gene Environment Association Studies Genes and Environment Initiative Study of Addiction: Genetics and Envi- ronment (SAGE) dataset’s embargo policy. The SAGE data access agreement states that investigators agree not to submit findings of the SAGE dataset(s) for publication until September 23, 2009. The authors sincerely apologize for this violation of SAGE policy. Xiang Chen Kelly Cho Burton H. Singer Heping Zhang www.pnas.org/cgi/doi/10.1073/pnas.0910252106 CORRECTION RETRACTION NEUROSCIENCE AND CORRECTION Correction for ‘‘Stomach ghrelin-secreting cells as food- entrainable circadian clocks,’’ by Joseph LeSauter, Nawshin Hoque, Michael Weintraub, Donald W. Pfaff, and Rae Silver, which appeared in issue 32, August 11, 2009, of Proc Natl Acad Sci USA (106:13582–13587; first published July 24, 2009; 10.1073/ Ϫ Ϫ pnas.0906426106). Fig. 2. Running wheel behavior of wild-type and GHSR / mice during ad The authors note that on page 13583, in the legend for Fig. 2, libitum feeding, food restriction, and food deprivation conditions. (A) The bar above the actograms shows the light–dark cycle; time of food availability is an equation appeared incorrectly. The figure and its corrected shown in gray. Actograms depict activity of representative GHSRϩ/ϩ and legend appear below. Additionally, in Fig. 3A on page 13584, the GHSRϪ/Ϫ mice during ad libitum feeding (days 1–4), food restriction ZT6–ZT14 panels labeled ‘‘Ghrelin’’ and ‘‘PER1’’ appeared incorrectly. The (days 4–15), ad libitum food availability (days 15–18), and food deprivation corrected figure and its legend appear below. These errors do not (day 19). (B) Group activity profiles show the amount of wheel running during affect the conclusions of the article. the last 7 days of restricted feeding in GHSRϩ/ϩ (black) and GHSRϪ/Ϫ (gray) mice. The data are plotted in 10-min bins (mean Ϯ SEM). **, P ϭ 0.002, difference between GHSRϩ/ϩ and GHSRϪ/Ϫ in onset time of activity. (C) Line graph of cumulative wheel-running activity (mean Ϯ SEM) from lights on (ZT0) to time of food presentation (ZT6) shows that GHSRϪ/Ϫ mice (solid gray line) ran 42.4% less than GHSRϩ/ϩ (solid black line) mice. Superimposed are the curves derived from the Gaussian function f(x) ϭ eϪx2/2/͌2␲ (dashed lines). (D) The anticipation ratios during 7 days of restricted feeding (Top) and the persistence ratio (Middle) on the day of food deprivation are shown for GHSRϪ/Ϫ (gray bars) and control GHSRϩ/ϩ (black bars) mice, with significant differences between groups. (Bottom) Daily activity during the period of food restriction. *, P ϭ 0.02; **, P ϭ 0.01. www.pnas.org PNAS ͉ October 6, 2009 ͉ vol. 106 ͉ no. 40 ͉ 17241–17242 Downloaded by guest on September 25, 2021 See Retraction Published September 9, 2009 PKNOX2 gene is significantly associated with substance dependence in European-origin women Xiang Chena,1, Kelly Choa,1, Burton H. Singerb,2, and Heping Zhanga,2 aDepartment of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520-8034; and bOffice of Population Research, Princeton University, Princeton, NJ 08544 Contributed by Burton H. Singer, August 1, 2009 (sent for review March 18, 2009) Substance dependence is a complex environmental and genetic dis- dependence phenotype that may not be apparent when individ- order that results in serious health and socioeconomic consequences. ual addiction conditions are considered. A review of this topic is Many studies have reported and implicated genes associated with given by Li and Burmeister (21). The availability of the Gene various substance dependence outcomes, including addiction to nic- Environment Association Studies Genes and Environment Ini- otine and addiction to alcohol. Using data from several genome-wide tiative Study of Addiction: Genetics and Environment (SAGE) case-control studies, we conducted a genome-wide association study data provides an unprecedented opportunity to study the ge- of a composite substance dependence phenotype derived from six netics of a composite trait: namely, addiction to at least two of individual diagnoses: addiction to nicotine, alcohol, marijuana, co- the six substances under study (nicotine, alcohol, marijuana, caine, opiates, or other drugs as a whole. We identified a strong (odds cocaine, opiates, and other drugs). -7E-8) association signal with In this report, we present a significant association at the genome ؍ and significant (P value (1.77 ؍ ratio the PBX/knotted 1 homeobox 2 (PKNOX2) gene on chromosome 11 in wide level (␣ ϭ 0.05) of the PKNOX2 gene on chromosome 11 with European-origin women with the composite phenotype. Our findings substance dependence in European-origin women. PKNOX2 has also indicate that the associations are not as significant when indi- been previously identified as one of the cis-regulated genes for vidual outcomes for addiction are considered, underscoring the im- alcohol addiction in mice (22). However, to our knowledge, portance of considering multiple addiction types. PKNOX2 has not been reported to be associated with any sub- stance addiction outcomes in human populations. We have iden- GENETICS comorbidity ͉ genetics of addiction ͉ genomewide association tified a cluster of markers in the region of the PKNOX2 gene that are strongly associated with a composite addiction at the genome- here is strong evidence that vulnerability to substance de- wide level. We also investigate potential sex-specificity and racial Tpendence or addiction (drugs, alcohol, or smoking) is a differences in the association. complex trait with both genetic and environmental components Results (1–3). Whether legal or illicit, substance abuse is one of the most sought-after phenomena in many populations because of its Table 1 summarizes the top eight significant SNPs which cluster serious health and socioeconomic consequences. In 2008, the in PKNOX2 on chromosome 11 (11q24). None of the eight SNPs Centers for Disease Control and Prevention estimated that violates the Hardy-Weinberg equilibrium assumption (minimum SOCIAL SCIENCES ϭ ϭ 443,000 deaths were caused by cigarette smoking and exposure P level 0.12). The most significant SNP (rs12284594; P to second-hand smoke (4). In addition, alcohol misuse has been 7.13E-08) is observed in white women with an odds ratio (OR) linked to attempted and successful suicide, particularly among of 1.77; thus, those who have the risk allele (G) for rs12284594 adolescents (5). Clearly, a better understanding of the genetics are at significantly increased risk of being diagnosed with at least behind vulnerability to addictions could tremendously improve two of the six categories of substance dependence. This P value overall health and quality of life in general. A useful start in this reaches the accepted genome-wide significance level (23). In direction is given by Kreek et al. (6) In the literature, candidate addition, there are seven other SNPs with P values less than genes for addiction to alcohol, nicotine, and other substances 3.8E-06 in white women, and the corresponding ORs are similar individually have been identified. For example, GABRA2, in magnitude (1.63–1.72). We also examined haplotypes in this CHRM2, and ADH4 are well studied for alcohol addiction and region, but they did not enhance the strength of the associations; have been replicated in many samples (7–10), while several hence, these results are not reported here. Similarly, when newer candidate genes, such as GABRG3, TAS2R16, SNCA, related individuals were included in the analysis, the strength of OPRK1, and PDYN, remain to be confirmed (11). Many variants association was not enhanced, whether the analysis was per- at the aldehyde dehydrogenase (ALDH) and alcohol dehydro- formed using PedGenie (24), or whether the correlation among genase (ADH) loci have also been well-documented, especially related individuals was ignored. Although we also observed that in East-Asian populations (12–15). Several studies also report a these eight SNPs confer increased risk in white men, black men, gene cluster of nicotinic acetylcholine receptors (CHRNA5, and black women, they fail to reach genome-wide significance. CHRNA3, and CHRNB4) and Neurexin1 show allelic differ- Hence, detailed results are not presented here for these groups. ences in heavy vs. light smokers (16–19). Li (20) reported 13 Additional analyses were performed to examine each sub- regions on chromosomes 3–7, 9–11, 17, 20, and 22 to be stance dependence outcome separately for the top eight SNPs significantly associated with nicotine dependence in at least two presented above. The corresponding P values for the eight SNPs for each substance dependence outcome are presented in Table independent samples, although a significant number of reported ϭ genomic regions did not reach the level of ‘‘suggestive’’ or 2. Alcohol dependence shows the strongest association (P ‘‘significant’’ linkage and failed to be replicated in other inde- pendent studies. Author contributions: X.C., K.C., and H.Z. designed research; X.C., K.C., B.H.S., and H.Z. Although individually different substance dependence out- performed research; X.C., K.C., and H.Z. contributed new reagents/analytic tools; X.C., K.C., comes have been previously studied, substance dependence as a and H.Z. analyzed data; and X.C., K.C., B.H.S., and H.Z. wrote the paper. whole, combining addiction to nicotine, alcohol, marijuana, The authors declare no conflict of interest. cocaine, opiates, and other drugs, has not been thoroughly 1X.C. and K.C. contributed equally to this work.