Meta-Analysis of Case-Control and Family-Based Associations Between the 5-HTTLPR L/S Polymorphism and Susceptibility to ADHD

Abstract

Objective: The aim of this study was to determine whether the serotonin transporter-linked polymorphic region (5-HTTLPR) L (long)/S (short) polymorphism is associated with susceptibility to ADHD. Method: We conducted a meta-analysis of case-control associations and the transmission disequilibrium test (TDT) between the 5-HTTLPR L/S polymorphism and ADHD. Results: A total of 19 comparison studies were included in this meta-analysis. Our meta-analysis of the case-control studies showed no association between ADHD and the 5-HTTLPR S allele, for all study participants (odds ratio [OR] = 1.075, 95% confidence interval [CI] = [0.990, 1.167], p = .085), or for the European or Asian population. The TDT indicated no association between ADHD and the 5-HTTLPR S allele, for all study participants (OR = 1.078, 95% CI = [0.962, 1.207], p = .196). Conclusion: This meta-analysis of case-control studies and TDT showed a lack of association between the 5-HTTLPR L/S polymorphism and ADHD.

Keywords

ADHD 5-HTTLPR polymorphism meta-analysis

Introduction

ADHD is a common neurobehavioral disorder that is characterized by hyperactivity, impulsiveness, and a lack of attention. ADHD emerges during childhood, usually before 7 years of age, and has a prevalence of up to 5% of children worldwide (Franke et al., 2012). Although ADHD is complex and heterogeneous, and its etiology has not been determined, genetic susceptibility to ADHD has been identified in case-control, twin, and family studies (Mick & Faraone, 2008). Linkage analysis is a method for identifying the presence of susceptibility genes for ADHD within the regions of chromosome. Transmission disequilibrium test (TDT) using linkage disequilibrium combines tests of linkage and allelic association. Case-control study evaluates the association between ADHD and susceptible genetic variants. Linkage studies showed heterogeneity of linkages, such as chromosome 2q24, 5p12, 10q26, 12p13, 12q23, and 16p (Fisher et al., 2002), and association studies using TDT and case-control studies revealed genetic heterogeneity, such as dopamine transporter, dopamine D4 receptor, tachykinin receptor 1, serotonin 1B receptor, alpha2A and 1A adrenergic receptors, and monoamine oxidase A (Sharp, McQuillin, & Gurling, 2009).

Serotonin (5-hydroxytryptamine, 5-HT) is a key neurotransmitter in the central nervous system. The serotonin transporter (5-HTT) gene, SLC6A4, has been reported to be involved in the pathogenesis of major psychiatric disorders, including anxiety, depression, schizophrenia, and autism (Graeff, 1997). A 44-bp insertion or deletion in the 5′-flanking promoter region of the 5-HTT gene (the 5-HTT-linked polymorphic region, 5-HTTLPR) creates a long (L) and a short (S) allele, having 16 and 14 repeat elements, respectively (Heils et al., 1996). The S variant is associated with reduced transcriptional efficiency of the 5-HTT gene promoter, resulting in lowered 5-HT reuptake activity, compared with the L variant. Studies revealed increased serotonin uptake, transporter expression, and efficiency of transcription in case of the LL genotype rather than the SS genotype in human lymphoblast cells (Bradley, Dodelzon, Sandhu, & Philibert, 2005; Lesch et al., 1996).

Case-control studies have shown an association between candidate polymorphisms and ADHD. In addition, a family-based study using the TDT was robust against spurious associations due to population stratification (Spielman, McGinnis, & Ewens, 1993). The 5-HTTLPR L/S polymorphism has been studied several times in the context of ADHD, using case-control and TDT analyses. Manor et al. showed an association between the functional 5-HTTLPR L/S polymorphism and ADHD (Manor et al., 2001), but published results for genetic association of the 5-HTTLPR L/S polymorphism are controversial and inconclusive (Lee, Woo, Choi, Ji, & Song, 2010a, 2010b; Nath, Harley, & Lee, 2005), which may be due to small sample size, low statistical power, and/or clinical heterogeneity. Therefore, to overcome the limitations of individual studies, resolve inconsistencies, and reduce the likelihood that random errors are responsible for false-positive or false-negative associations, we turned to meta-analysis (Lee, Harley, & Nath, 2006; Lee, Rho, Choi, Ji, & Song, 2006; Lee et al., 2007). In the present study, we investigated whether the 5-HTTLPR L/S polymorphism is associated with susceptibility to ADHD, using a meta-analysis of case-control studies and the TDT.

Method

Identification of Eligible Studies and Data Extraction

Using the MEDLINE and EMBASE citation databases, we performed a literature search to identify papers published up to February 2014 that examined associations between the 5-HTTLPR L/S polymorphism and ADHD. Combinations of keywords such as “5-HTTLPR,” “attention-deficit/hyperactivity disorder,” and “ADHD” were entered as Medical Subject Heading terms and text words. References within the identified papers were used to identify additional studies not indexed by the electronic databases. Inclusion criteria were as follows: (a) case-control or family-based study design, (b) original data, and (c) sufficient data to calculate odds ratios (ORs). No language restriction was applied. The following information was extracted from each identified study: (a) author and year of publication, (b) ethnicity and demographics of the study population, (c) numbers of cases and controls for the 5-HTTLPR L/S polymorphism, and (d) frequency of transmission or non-transmission of the S allele of the 5-HTTLPR L/S polymorphism to affected offspring. Allele frequencies were calculated from the corresponding genotype distributions.

Evaluation of Statistical Associations

Meta-analyses of case-control studies were performed using allele contrast, in which the numbers of allele S are compared with those of allele L (S vs. L), and homozygote contrast, in which the SS genotype is compared with the LL genotype (SS vs. LL), and recessive and dominant models, and subgroup analyses were performed according to ethnicity. We also conducted the TDT, examining transmission of one allele (the transmitted allele) of the 5-HTTLPR L/S polymorphism to children who developed ADHD. The TDT is used to test the null hypothesis of no association between alleles that are transmitted and those that are not transmitted to affected offspring. The TDT in parent–offspring trios is algebraically equivalent to treating the number of transmissions of each allele as the number of occurrences of that allele in cases, and to considering the controls to be a very large population with equal numbers of each allele (reflecting the expected 50:50 transmission ratio). As the studies analyzed here are family-based, we used the McNemar chi-square test, comparing the number of times the allele is transmitted with the theoretical number of times it should be transmitted according to a 50% chance of transmission (Spielman et al., 1993); a significant test result provides evidence that the marker is associated with the disease locus. Point estimates of risks, ORs, and 95% confidence intervals (CIs) were estimated for each study. Cochran’s Q-statistic was used to assess within- and between-study variation or heterogeneity. The heterogeneity test was used to assess the null hypothesis that all studies evaluated the same effect. I² values were used to quantify heterogeneity. I² values ranged between 0% and 100%, and represented the proportion of between-study variability attributable to heterogeneity rather than chance (Higgins & Thompson, 2002). I² values of 25%, 50%, and 75% were nominally assigned as low, moderate, and high estimates, respectively. The fixed effects model assumes that a genetic factor would have the same effect on ADHD susceptibility across all studies investigated and was used to assess whether variations between studies were caused by chance alone. The random effects model assumes that different studies have substantial diversity, and was used to assess within-study sampling error and between-study variance. For homogeneous study groups, the two models were similar, but when this was not the case, the random effects model generated wider CIs than the fixed effects model. The random effects model was used where there was significant heterogeneity between studies (DerSimonian & Laird, 1986). Statistical manipulations were performed using the Comprehensive Meta-Analysis software (Biostat, Englewood, NJ, USA).

Evaluation of Publication Bias

Studies reporting positive effects tend to have a higher likelihood of being published than those that do not, and studies showing no significant result tend to remain unpublished (Dickersin & Min, 1993). As meta-analysis includes only published studies, the degree of the actual effect might be overestimated (Dickersin & Min, 1993). This outcome is termed “publication bias.” While funnel plots are often used to detect publication bias, funnel plotting requires a range of studies of varying sizes and involves subjective judgments. Accordingly, we evaluated publication bias using Egger’s linear regression test (Egger, Davey Smith, Schneider, & Minder, 1997), which measures funnel plot asymmetry using a natural logarithm scale of ORs.

Results

Studies Included in the Meta-Analysis

Ninety studies were identified by electronic or manual searching, and 19 were selected for a full-text review, based on their title and abstract details. Seven studies were excluded because they were reviews, or because they did not contain genotype or control data. Thus, 12 studies met the inclusion criteria (Banerjee et al., 2006; Grevet et al., 2007; Heiser et al., 2007; Kim et al., 2005; Landaas et al., 2010; Langley et al., 2003; Li et al., 2007; Manor et al., 2001; Xu et al., 2008; Xu et al., 2005; Zhao et al., 2005; Zoroglu et al., 2002; Figure 1). Of these, 1 study contained data on six different ethnic groups (Landaas et al., 2010), 1 study contained data on two different ethnic groups (Xu et al., 2005), and 2 studies included both case-control and family-based data (Kim et al., 2005; Langley et al., 2003); in the present study, ethnic groups and case-control/family-based data were independently analyzed. Two comparisons were excluded, because of insufficient data or data duplication. In total, 18 separate comparisons were considered in this meta-analysis. Eleven studies (6 in Europeans, 2 in Asians, and 1 each in the Turkish, Jewish, and an unknown population) with a total of 1,640 cases and 1,066 controls were case-control studies of the 5-HTTLPR L/S polymorphism, and 7 studies (3 in Europeans and 4 in Asians) with a total of 1,979 transmissions of the 5-HTTLPR S allele were family-based studies. Ethnicity-specific meta-analysis was conducted on European and Asian populations. Selected characteristics of the studies included in the meta-analysis, and the relationships found between the 5-HTTLPR L/S polymorphism and ADHD are summarized in Table 1.

Figure 1.

Flowchart for the selection of studies.

Table 1.

Characteristics of Studies in the Meta-Analysis.

A. Case-Control Study of the 5-HTTLPR L/S Polymorphism.

Author (ref)	Ethnicity	No. of participants		5-HTTLPR S allele (%)		Allele association
Author (ref)	Ethnicity	Case	Control	Case	Control	OR	95% CI		p value
Landaas-1, 2010 (Landaas et al., 2010)	Caucasian	448	580	44.0	40.0	1.177	0.987	1.405	.070
Landaas-2, 2010 (Landaas et al., 2010)	Caucasian	589	393	NA	NA	0.970	0.790	1.191	.771
Landaas-3, 2010 (Landaas et al., 2010)	Caucasian	246	490	NA	NA	1.050	0.810	1.361	.712
Landaas-4, 2010 (Landaas et al., 2010)	Caucasian	299	312	NA	NA	1.140	0.857	1.516	.367
Landaas-5, 2010 (Landaas et al., 2010)	Unknown	320	107	NA	NA	1.100	0.798	1.516	.561
Grevet, 2007 (Grevet et al., 2007)	Caucasian	312	236	47.6	44.5	1.133	0.891	1.441	.307
Zhao, 2005 (Zhao et al., 2005)	Asian	135	110	74.1	76.4	0.884	0.585	1.337	.560
Kim, 2005 (Kim et al., 2005)	Asian	125	532	73.2	72.1	1.058	0.776	1.442	.723
Langley, 2003 (Langley et al., 2003)	Caucasian	142	118	44.4	45.3	0.961	0.679	1.360	.824
Zoroglu, 2002 (Zoroglu et al., 2002)	Turkish	70	120	49.3	55.0	0.795	0.524	1.207	.282
Manor, 2001 (Manor et al., 2001)	Jewish	998	68	46.8	39.0	1.380	0.967	1.970	.076

Note. 5-HTTLPR = 5-hydroxytryptamine transporter-linked polymorphic region; L/S = long/short; ref = reference; OR = odds ratio; CI = confidence interval; NA = not available.

B. Family-Based Association Study.

Author (Ref)	Ethnicity	5-HTTLPR S allele		Expected distribution		Allele association
Author (Ref)	Ethnicity	T	NT	T	NT	OR	95% CI		p value
Xu, 2008 (Xu et al., 2008)	Caucasian	462	496	479	479	0.931	0.779	1.114	.437
Heiser, 2007 (Heiser et al., 2007)	Caucasian	161	140	151	151	1.142	0.830	1.573	.415
Li, 2007 (Li et al., 2007)	Asian	118	83	101	101	1.408	0.949	2.087	.089
Banerjee, 2006 (Banerjee et al., 2006)	Asian	161	114	138	138	1.402	1.001	1.964	.049
Kim, 2005 (Kim et al., 2005)	Asian	36	52	44	44	0.692	0.381	1.256	.227
Xu, 2005 (Xu et al., 2005)	Asian	36	42	39	39	0.857	0.457	1.607	.631
Langley, 2003 (Langley et al., 2003)	Caucasian	43	35	39	39	1.229	0.655	2.305	.521

Note. ref = reference; 5-HTTLPR = 5-hydroxytryptamine transporter-linked polymorphic region; T = transmitted (number of times the allele is transmitted from heterozygous parents to the probands); NT = not transmitted; OR = odds ratio; CI = confidence interval.

Meta-Analysis of Case-Control Studies of the 5-HTTLPR L/S Polymorphism and ADHD

Meta-analysis was performed for a combined population of patients with ADHD and by each individual ethnic category. No association was observed between ADHD and the 5-HTTLPR S allele for the combined study participants (OR = 1.075, 95% CI = [0.990, 1.167], p = .085; Table 2, Figure 2). Ethnicity-specific meta-analysis indicated no association between the 5-HTTLPR S allele and ADHD, in either the European (OR = 1.083, 95% CI = [0.984, 1.192], p = .102) or Asian (OR = 0.992, 95% CI = [0.774, 1.271], p = .947) population (Table 2). In addition, analysis using recessive, dominant, or homozygote contrast models showed the same pattern for the 5-HTTLPR S allele (Table 2).

Table 2.

Analysis of the Association Between the 5-HTTLPR L/S Polymorphism and ADHD.

A. Case-Control Study.

Polymorphism	Population	No. of studies	No. of participants		Test of association			Test of heterogeneity
Polymorphism	Population	No. of studies	Case	Control	OR	95% CI	p value	Model	p value	I ²
5-HTTLPR	Overall	11	3,684	3,066	1.075	[0.990, 1.167]	.085	F	.673	0
S vs. L	European	6	2,036	2,129	1.083	[0.984, 1.192]	.102	F	.740	0
	Asian	2	260	642	0.992	[0.774, 1.271]	.947	F	.497	0
SS + SL vs. LL	Overall	5	1,640	1,066	1.246	[0.962, 1.613]	.095	F	.853	0
(dominant)	European	1	312	236	1.231	[0.831, 1.806]	.288	NA	NA	NA
	Asian	2	260	642	1.103	[0.592, 2.053]	.758	F	.524	0
SS vs. SL + LL	Overall	5	1,640	1,066	0.975	[0.663, 1.435]	.899	R	.034	61.4
(recessive)	European	1	312	236	1.356	[0.746, 1.791]	.517	NA	NA	NA
	Asian	2	260	642	0.964	[0.707, 1.314]	.815	F	.241	27.3
SS vs. LL	Overall	5	1,640	1,066	1.226	[0.877, 1.714]	.233	F	.354	9.22
	European	1	312	236	1.312	[0.784, 2.194]	.301	NA	NA	NA
	Asian	2	260	642	1.077	[0.570, 2.035]	.819	F	.746	0

Note. 5-HTTLPR = 5-hydroxytryptamine transporter-linked polymorphic region; L/S = long/short; OR = odds ratio; CI = confidence interval; F = fixed effects model; R = random effects model; NA = not available.

B. Family-Based Association Study.

Polymorphism	Population	No. of studies	Test of association			Test of heterogeneity
Polymorphism	Population	No. of studies	OR	95% CI	p value	Model	p value	I ²
5-HTTLPR S	Overall	7	1.054	[0.930, 1.194]	.410	F	.150	36.5
T vs. NT allele	European	3	0.991	[0.852, 1.153]	.907	F	.435	0
	Asian	4	1.200	[0.963, 1.496]	.105	F	.121	48.4

Note. OR = odds ratio; CI = confidence interval; 5-HTTLPR = 5-hydroxytryptamine transporter-linked polymorphic region; T = transmitted (from heterozygous parents to the probands); NT = not transmitted; F = fixed effects model.

Figure 2.

ORs and 95% CIs of studies and pooled data for the allelic association between the 5-HTTLPR L/S polymorphism and ADHD in all study participants.

Meta-Analysis of Family-Based Studies of the 5-HTTLPR L/S Polymorphism and ADHD

A summary of the meta-analysis findings of the TDT for association between the 5-HTTLPR L/S polymorphism and ADHD is provided in Table 2. Meta-analysis showed no association between the 5-HTTLPR S allele and ADHD (OR = 1.054, 95% CI = [0.930, 1.194], p = .410; Table 2, Figure 2). Stratification by ethnicity indicated no association between the 5-HTTLPR S allele and ADHD in either the European (OR = 0.991, 95% CI = [0.852, 1.153], p = .907) or Asian (OR = 1.200, 95% CI = [0.963, 1.496], p = .105) population (Table 2, Figure 3).

Figure 3.

ORs and 95% CIs of studies and pooled data for the family-based association between the S allele of the 5-HTTLPR L/S polymorphism and ADHD in all study participants.

Heterogeneity and Publication Bias

The Hardy–Weinberg equilibrium (HWE) refers to a situation in which the frequencies of genotypes are predicted on the basis of the frequencies of two alleles according to the simple Mendelian inheritance model (Wittke-Thompson, Pluzhnikov, & Cox, 2005). Departures from HWE can arise from genotyping errors, population stratification, and selection bias in the recruitment of controls (Salanti, Amountza, Ntzani, & Ioannidis, 2005). Whether the genotype frequencies of the controls are in HWE must be determined, because genotyping errors are a significant cause of deviation from HWE. Sensitivity analysis was performed according to HWE status; however, excluding those studies not in HWE did not materially affect our results. No between-study heterogeneity was found in the meta-analysis of association of the 5-HTTLPR L/S polymorphism that included all study participants, except for the analysis of the 5-HTTLPR L/S polymorphism in the recessive model (Table 2). Funnel plots to detect publication bias were difficult to correlate because of the small number of studies included in the meta-analysis; however, Egger’s linear regression test showed no evidence of publication bias in the meta-analysis (Egger’s linear regression test p values were >.1).

Discussion

Studies have been carried out on the roles of polymorphisms in genes that encode components of the serotoninergic system in ADHD. We combined evidence on the association of the 5-HTTLPR L/S polymorphism and susceptibility to ADHD in this meta-analysis, and found no association between the 5-HTTLPR L/S polymorphism and ADHD susceptibility in the analyzed European or Asian populations. In addition, none of the genetic models for case-control studies that we used, or family-based tests, detected association between the 5-HTTLPR L/S and ADHD susceptibility, in the combined study participants, or in the European or Asian population.

In addition to case-control studies, our meta-analysis also examined transmission disequilibrium in families using the TDT. The TDT is less efficient than case-control analysis in detecting a moderate effect of susceptibility genes but is largely protected from stratification bias. Our meta-analysis of family-based associations using the TDT confirmed that there was no association between the 5-HTTLPR L/S polymorphism and ADHD, consistent with our findings from the meta-analysis of case-control studies.

Our meta-analysis does not support an important role of the 5-HTTLPR L/S polymorphism in susceptibility to ADHD. The results of our meta-analysis are not consistent with those of functional studies of the 5-HTTLPR L/S polymorphism. In general, disagreements between epidemiological and functional studies of ADHD are not entirely unexpected, given that it is a complex disease that involves multiple genes, genetic backgrounds, and environmental factors. In our case, the discrepancy with functional studies may arise from mixed clinical subtypes or different neurological lesions in the study populations, and further studies are required to examine this possibility. Thus, it is possible that the results of our 5-HTTLPR meta-analysis are due to Type II errors (false negatives).

This meta-analysis differs from a previous meta-analysis on the relationship between the 5-HTTLPR L/S polymorphism and ADHD risk performed by Landaas et al. (2010); in the present meta-analysis, additional six studies, representing 1,782 new patients with ADHD and 1,184 more controls, were included and meta-analysis was also conducted on families. The analytic method used in the present meta-analysis of case-control studies was same as that used in the previous one, but the analytic method used in our meta-analysis of family studies was a new one. However, the results of our meta-analysis, showing no association between the 5-HTTLPR L/S polymorphism and the development of ADHD, are in agreement with those of this previous study.

Our meta-analysis has several limitations. First, heterogeneity and other confounding factors might have affected our findings. Second, our ethnicity-specific analysis only included data from European and Asian patients with ADHD; therefore, the results are only applicable to these ethnic populations. Third, it would have been interesting to evaluate the association between the 5-HTTLPR polymorphism and 5-HTT activity or clinical features of ADHD, but this was not possible owing to the limited data. Finally, the number of studies included in the subgroup analysis by ethnicity was small. There were only two studies of the 5-HTTLPR L/S polymorphism in Asian patients with ADHD among the case-control studies and three studies in European patients with ADHD in the TDT; the study numbers in the ethnicity-specific meta-analysis may not be sufficient to provide a conclusive result.

In conclusion, this meta-analysis demonstrates that 5-HTTLPR L/S polymorphism is not associated with susceptibility to ADHD in European or Asian populations. These data do not support the hypothesis that the 5-HTTLPR L/S polymorphism plays an important role in susceptibility to ADHD. Larger studies in homogeneous populations of different ethnicity are necessary to investigate the roles of the 5-HTTLPR L/S polymorphism in the pathogenesis of ADHD.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Author Biographies

Young Ho Lee is a professor of the Department of Rheumatology, Anam Hospital, at Korea University, College of Medicine. His research interests are meta-analysis and systematic review, and clinical studies.

Gwan Gyu Song is a professor and head of the Department of Rheumatology, Guro Hospital, at Korea University, College of Medicine. His research interests include systematic review and clinical studies.

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