Psychiatry Research 219 (2014) 10–24

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Psychiatry Research

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Review article Molecular genetic studies of ADHD and its candidate : A review

Zhao Li a,b,1, Su-hua Chang a,1, Liu-yan Zhang a,b,1, Lei Gao a,b, Jing Wang a,n a Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, 16 Lincui Road, Chaoyang District, Beijing 100101, China b University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China article info abstract

Article history: Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder with Received 19 November 2013 high heritability. In recent years, numerous molecular genetic studies have been published to investigate Received in revised form susceptibility loci for ADHD. These results brought valuable candidates for further research, but they also 31 March 2014 presented great challenge for profound understanding of genetic data and general patterns of current Accepted 4 May 2014 molecular genetic studies of ADHD since they are scattered and heterogeneous. In this review, we Available online 10 May 2014 presented a retrospective review of more than 300 molecular genetic studies for ADHD from two Keywords: aspects: (1) the main achievements of various studies were summarized, including linkage studies, fi Attention-de cit/hyperactivity disorder candidate- association studies, genome-wide association studies and genome-wide copy number Linkage study variation studies, with a special focus on general patterns of study design and common sample features; Association study (2) candidate genes for ADHD have been systematically evaluated in three ways for better utilization. The Study design Sample characteristics thorough summary of the achievements from various studies will provide an overview of the research status of molecular genetics studies for ADHD. Meanwhile, the analysis of general patterns and sample characteristics on the basis of these studies, as well as the integrative review of candidate ADHD genes, will propose new clues and directions for future experiment design. & 2014 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction...... 10 2. Molecular genetic studies of ADHD and main achievements ...... 11 2.1. Genetic linkage studies ...... 11 2.2. Candidate-gene association studies ...... 12 2.3. Genome-wide association studies...... 14 2.4. Copy number variation studies ...... 15 3. Evaluation of candidate genes for ADHD ...... 16 3.1. Hotgenes...... 16 3.2. Multi-evidence supported genes...... 16 3.3. Prioritized genes ...... 18 4. Conclusion...... 19 Acknowledgments...... 19 Appendix A. Supporting materials ...... 19 References...... 19

1. Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a common n Corresponding author. Tel./fax: þ86 10 64855841. psychiatric disorder which is characterized by continuous and age- E-mail address: [email protected] (J. Wang). fi 1 The authors Zhao Li, Su-hua Chang and Liu-yan Zhang have contributed inappropriate de ciency in sustained attention and/or hyperactive, equally to this study. impulsive behaviors (Banaschewski et al., 2010). With a worldwide http://dx.doi.org/10.1016/j.psychres.2014.05.005 0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved. Z. Li et al. / Psychiatry Research 219 (2014) 10–24 11 prevalence of about 5% (Polanczyk et al., 2007a), ADHD usually most promising candidate genes for ADHD predicted by gene begins in early childhood and affects 8–12% of school-age children prioritization analysis. By incorporating these works, the current (Biederman and Faraone, 2005). Symptoms often persist into review article is not only a collection of previous results, but also a adolescence and may even continue into adulthood among 80% systematic overview and evaluation for ADHD candidate genes. It of children with ADHD (Faraone et al., 2003). ADHD might inflict will facilitate understanding the research status and study design long-term harm on patients like low self-esteem, substance abuse, of ADHD molecular genetic studies, as well as candidate selection delinquency and psychological dysfunction, which causes a heavy in future research. burden to families and society (NIH, 2000). It has been well known that ADHD is a complex condition caused by a number of factors including genetic, social and 2. Molecular genetic studies of ADHD and main achievements physical environment (Thapar et al., 2013). Due to its complex heterogeneity, the specific causes of ADHD are not yet clearly 2.1. Genetic linkage studies identified. Evidences from family, twin, adoption and association studies consistently indicate that genetic factors play a substantial Since 2002, there have been 15 linkage studies performed for role in the etiology of ADHD with a mean heritability estimate of ADHD to screen the genetic loci involved in this disease, including 76% (Biederman, 2005; Faraone et al., 2005; Kuntsi and Stevenson, 12 genome-wide linkage (GWL) analyses (Table 1), two fine map- 2000). Increasing association studies, especially genome-wide ping studies of previously reported regions (Ogdie et al., 2004; association studies (GWAS), indicate that multiple genes with Smalley et al., 2002) and one mapping study of specific locus with moderate effects should be responsible for conferring susceptibil- the three gene, LPHN3 (Arcos-Burgos et al., 2010a). ity to ADHD (Tripp and Wickens, 2009). Numerous molecular Among 12 GWL studies, eight were conducted within sib-pair genetics researches, mainly including linkage studies (Zhou et al., samples and four in large pedigrees. Linkage analysis with large 2008), candidate-gene association studies (CGAS) (Gizer et al., pedigrees is powerful to identify high-penetrance variants and 2009), genome-wide association studies (Neale et al., 2010b), copy effective to prevent errors raised by etiologic heterogeneity, but number variation (CNV) studies (Williams et al., 2010) as well as not so efficient for low-penetrance variants, like common variants exome sequencing studies (Lyon et al., 2011) have been carried out with modest effects (Freimer and Sabatti, 2004; Garner et al., 2001). to explore the genetic susceptibility of ADHD. As a consequence, Besides, the difficulty in collecting large pedigree samples is also an hundreds of genetic markers have been identified as valuable issue to consider for linkage analysis. In contrast, sib-pair samples candidates for further research (Gizer et al., 2009; Maher et al., have the advantages of easier sample collection so that the sample 2002; Michaelovsky et al., 2008; Neale et al., 2010b; Zhou et al., size could be growing large enough to improve the power of linkage 2008). However, few definite conclusions were made to elucidate tests. So far, all of the GWL studies for ADHD were conducted in which genes influence the occurrence and inheritance of ADHD, Caucasian populations except for one in a genetic isolate of the self- since these results are scattered and often inconsistent. The designated “Paisa” community (Arcos-Burgos et al., 2004). It would excessive accumulation and complicated heterogeneity of these be necessary to perform linkage analysis in different ethnicity studies have driven a growing need to make a retrospective review populations to build a full-scale linkage map for ADHD. by indexing the general patterns they followed and main achieve- With the publication of linkage studies, more than 100 differ- ments they have obtained. Moreover, sample size is one of the ent regions were reported for ADHD. Among them, 22 regions fundamental decisions in the design of genetic studies to achieve have been found owning statistically significant signals by GWL an adequate statistical power (Spencer et al., 2009). Racial and studies (Table 1) and two regions (6q12 (Ogdie et al., 2004) and ethnic categories are also important considerations in genetics 4q13.1 (Arcos-Burgos et al., 2010b)) were tested as significant by research since there are substantial, well-demarcated biological candidate region linkage studies. Regions 16p13 (Ogdie et al., differences among racial and ethnic groups, which might be an 2003; Smalley et al., 2002) and 17p11 (Arcos-Burgos et al., 2004; important cause of heterogeneity (Race and Genetics Working, Ogdie et al., 2004) are the most promising loci since they were 2005). Therefore, a full summary of sample characteristics of reported twice as significant linked loci with ADHD in one GWL published studies will provide scientific guidance for future study study and one candidate region linkage study respectively. How- design. In addition, abundant candidate genes have brought great ever, in general terms, few regions could be consistently repli- challenge to weigh their strength of associations with ADHD, and cated. To combine the results from various GWL studies and thus a comprehensive comparison and evaluation of reported improve the power of detecting genomic regions with consistent genes is eagerly needed. linkage evidence, two meta-analyses were conducted. One of them In this review, we try to demonstrate the aspects above about (Ogdie et al., 2006) pooled the genome-wide linkage data on 424 molecular genetic studies of ADHD in a literature mining way on ADHD affected sib pairs from two studies (Bakker et al., 2003; the basis of more than 300 publications, with the same inclusion Ogdie et al., 2004) and re-analyzed the pooled sample in two criteria as ADHD gene (Zhang et al., 2012). Here we only reviewed ways: simulation-based linkage estimation and un-weighted rank- publications about association studies, linkage studies, and meta- based genome search meta-analysis (GSMA) (Ogdie et al., 2006). analyses with target to identify genetic susceptibility factors of Both the pooled linkage analysis and GSMA indicated a lack of ADHD in diagnosed patients. Other publications about pharmacol- overlap of linkage peaks with the exception of 5p13. ogy, sociology, electrophysiology, neurophysiology and behavioral The other meta-analysis (Zhou et al., 2008) applied GSMA to seven research are beyond the scope of this review. In the first part of published ADHD GWL scans (Anney et al., 2008; Arcos-Burgos et this article, main results from different types of genetic studies al., 2004; Bakker et al., 2003; Faraone et al., 2008; Hebebrand et were summarized. Additionally, a special emphasis was put on the al., 2006; Ogdie et al., 2003; Romanos et al., 2008) with a total general pattern of study design and hints about sample character- number of cases up to two thousand. In this study, genome-wide istics. In the second part, candidate genes for ADHD were com- significant linkage was identified on between 64 pared and evaluated through systematic integration of reported and 83 Mb. Moreover, nine other regions were found showing genes from three aspects: (1) “hot genes” defined as candidate nominal or suggestive evidence of linkage with ADHD. genes reported by at least five studies. (2) “Multi-evidence With an effort to find overlaps with candidate genes, we supported genes” from intersection analysis of results from further mapped the literature-origin genes to the signification different types of genetic studies. (3) “Prioritized genes” as the regions from linkage studies and detected 29 literature-origin 12 Z. Li et al. / Psychiatry Research 219 (2014) 10–24

Table 1 Genome-wide linkage studies of ADHD (including meta-analysis).

No. Study Design Ethnicity Sample size Analysis Reported regions (literature-origin genes)c method

1 Fisher et al. (2002) ASP a Caucasian 126 ASPs from 104 families Non- 2q14, 2q24, 3q24, 4p15, 5p12, 7p15, 8p23, 9q21, 9q22, 10q26, 11q25, parametric 12p13, 12q23, 12q24, 13q12, 13q31, 13q33, 16p13, 16q21, 21q21, Xp22 2 Bakker et al. (2003) ASP Caucasian 164 ASPs from 106 families Non- 3q13.32, 4p16.3, 5p13.1, 6q26, 7p13, 9q33.3, 10cen, 13q33.3, 15q15.1s parametric 3 Ogdie et al. (2003) ASP Caucasian 270 ASPs from 204 families Non- 5p13, 6p12, 6q14, 11q13, 11q25, 15q26, 16p13 (GRIN2A, EMP2, parametric ZNF75A), 17p11, 17p12, 20q13 4 Arcos-Burgos et al. Pedigree Paisa 16 multigenerational families Parametric 4q13.2, 5q33.3 (ADRA1B), 8q11.23, 11q22 (MMP7, CNTN5), 17p11 (2004) and non- (MAP2K3) parametric 5 Hebebrand et al. (2006) ASP Caucasian 155 sib-pairs Parametric 5p (FGF10, SLC6A3, SLC1A3, GDNF, HCN1, TRIO), 6q, 7p, 8, 9q, 11q, and non- 12q, 17p parametric 6 Asherson et al. (2008) ASP Caucasian 276 affected siblings Non- Chr2:181.5cM, Chr2:34.5cM, 9q22, Chr11:69cM, Chr14:100 cM, parametric 16q12, 16q23, Chr21:61.4 cM, ChrX:141.9 cM 7 Faraone et al. (2008) ASP Caucasian 271 families with 1170 Non- Chr8:54.2cM, Chr8:93.4cM, Chr15:51.7cM individuals parametric 8 Romanos et al. (2008) Pedigree Caucasian 8 families with 191 Parametric 1q25.1, 1q25.3, 2q35, 5q13.1, 6q22-23 (IL20RA, DNAJA1P4, TAAR3), individuals and non- 7q21.11, 9q22 (CDK20, NFIL3, DIRAS2), 9q31.1-33.1 (ASTN2, TRIM32), parametric 9q33 (ASTN2, TRIM32), 12p13.33, 14q12 (PRKD1), 15q11.2-13.3 (CHRNA7), 16p12.3-12.2 (GPRC5B), 16q24.1, 18q11.2-12.3 9 Rommelse et al. (2008) ASP Caucasian 238 ADHD probands and their N/A d 2p25.1, 2p25.2, 2q14.3, 2q21.1, 3p24.3, 4q35.2, 8q22.3, 9p21.2, 112 affected and 195 non- 12p13.33, 12q23.3, 13q12.11, 14q32.13, 17q12 affected siblings 10 Amin et al. (2009) Pedigree Caucasian 9 patients Parametric 1p36, 5q33, 6p12, 6p22, 6q15, 15q25, 18p11, 18q21, 18q22 11 Vegt et al. (2010) Pedigree Caucasian 24 family members Parametric 7p15.1-q31.33, 14q11.2-22.3 and non- parametric 12 Saviouk et al. (2011) ASP Caucasian 711 families with 3412 non- Parametric 2p25.1 (ID2), 3p24.3-24.1, 8p23.3-23.2, 18q21.1-22.3, 18q21.31-21.32 clone individuals (CPLX4, MC4R) 13 Ogdie et al. (2006) Meta b Caucasian 424 ASPs from Bakker SC, N/A 5p13 (GDNF, SLC1A3) 2003 and Ogdie MN, 2003 14 Zhou et al. (2008) Meta b Caucasian 2084 cases from study 2-8 Non- 5p15.32-q14.3, 6p21.1-q15, 6q15-23.2, 7p14.1-q21.11, 8p23.3, parametric 9q21.32-31.1, 15p13, 16p13.3 (ZNF75A), 16q23.1-24.3 (ATP2C2, CDH13), 17p13.3

a ASP means affected sib pair. b Meta-analysis of genome-wide linkage studies. c Statistical significant regions are bolded and underlined. Literature-origin genes mapped to the significant regions are displayed in parentheses. d N/A denotes unavailable. genes (Table 1). Among which, SLC6A3 is the most extensively association varies and results are very inconsistent for the same investigated gene that has been reported by 70 studies (Table 4). locus, genes from several important pathways or systems have CDH13 (Lee, 1996), which encodes adhesion that affect obtained strong evidence for association with ADHD. The first type cell–cell interaction, has been investigated in both CGAS of pathways are three neurotransmission systems: Ribases et al. (Mavroconstanti et al., 2013) and GWASs (Lasky-Su et al., 2008b; tested nine genes in dopaminergic neurotransmission system and Lesch et al., 2008; Neale et al., 2010a), and thus it is worth more validated the association between DRD1 and ADHD (Ribases et al., attention in future research. GRIN2A (Kalsi et al., 1998), which 2012); the exploration of 19 serotoninergic candidate genes in encodes , ionotropic, N-methyl D-aspartate 2A, adults and children with ADHD identified association for HTR2A, has been reported by four CGASs with only one significant result DDC and MAOB (Ribases et al., 2009b); inspection of 14 noradre- (Adams et al., 2004; Nyman et al., 2007; Park et al., 2013; Turic et nergic genes showed evidence of association between SLC6A2, al., 2004). Other genes have been examined in only one or two ADRA1B and ADHD (Hawi et al., 2013). In addition, the evaluation studies and further replication is needed. Although linkage analy- of common variants in 16 genes involved in the regulation of sis is a useful method to make preliminary screening of suscept- release (Sanchez-Mora et al., 2013a) and 10 ibility loci for diseases, it is not so effective to identify specific genes encoding neurotrophic factors and their receptors (Ribases genes with modest effects for complex diseases. To better interpret et al., 2008) in ADHD showed the contribution of SNARE system the results from linkage studies of ADHD, fine mapping of the and neurodevelopment system to ADHD. Because of the theore- reported regions and related genes should be carried forward to tical hypothesis about the contribution of these pathways to confirm the association of these loci with ADHD. ADHD, the genes involved in these pathways were often tested together to validate the association of these pathways with ADHD. 2.2. Candidate-gene association studies Besides those genes in the well-known pathways or systems, some genes from other sources have also been recruited into Till now, CGASs have proposed nearly 180 candidate genes. candidate gene association study. For example, six genes asymme- About more than half of them were testified as significantly trically expressed in the two cerebral hemispheres were tested associated with ADHD in at least one study (Zhang et al., 2012). and the result supported the participation of BAIAP2 in ADHD There are many related review articles containing detailed infor- (Ribases et al., 2009a). The genetic result with mation about these candidate genes and their potential effects on support will facilitate the explanation of the gene function. ADHD (Banaschewski et al., 2010; Bobb et al., 2005; Coghill and Another example is microRNA genes. Because there has been Banaschewski, 2009; Sharp et al., 2009). Although the degree of growing interest in studying the role of microRNAs in the Z. Li et al. / Psychiatry Research 219 (2014) 10–24 13

Fig. 1. Sample size distribution of ADHD candidate-gene association studies. The studies with more than 1100 cases are plotted in the same line with number labels to optimize the figure. Studies with significant results or not are separated in red and blue respectively. Triangle, study with case-control design; circle dot, study with family- based design. The studies enrolled both case-control and family-based samples were counted into both groups. The proportion of studies with significant results for each bin of cases are marked on the right by using a colored progressive bar, the darker means the proportion is higher. N/A denotes unavailable. susceptibility to complex disorders, such as (Ripke family-based, and case-control strategies are displayed in Fig. 1, et al., 2011), Sánchez-Mora et al. evaluated several variants in the together with symbols implying whether significant results were miR-183-96-182 cluster in ADHD and substance use disorders and achieved by corresponding sample size. In general, studies using provided preliminary evidence for the contribution of two case-control strategy are increasing in recent years and studies sequence variants at the miR-183-96-182 cluster to ADHD without with larger sample size have higher proportion of generating comorbid SUD (Sanchez-Mora et al., 2013b). Moreover, since significant results. multiple genes with small effect sizes are assumed to play a role ADHD is a disorder with obvious sexual orientation, and is in ADHD, Bralten et al. proposed an approach to test the associa- more commonly diagnosed in boys than in girls with a ratio tion of multiple variants in a pathway as a whole (Bralten et al., ranging from 2:1 to 9:1 (Biederman et al., 2004; Cuffe et al., 2005). 2013) to increase the total explained phenotypic variance. These The candidate gene association studies of ADHD also follow this new avenues in the identification of candidate genes may generate pattern since nearly all of the studies recruited more males than novel and interesting results for the genetic basis of ADHD. females. There is a hypothesis that different genetic factors might Furthermore, to provide consistent evidence for association be responsible for ADHD males and females, but no direct with ADHD across studies, and to evaluate the overall effect evidence to support this opinion (Stergiakouli and Thapar, 2010). among results, many meta-analyses have been conducted on Results from genetic association studies of ADHD did not show candidate-gene association studies (Cheuk and Wong, 2006; clues inferring different genetic basis for boys and girls (Rhee et al., Forero et al., 2009; Li et al., 2006; Nikolaidis and Gray, 2010; 1999). On the other hand, the discrepant gender ratio between Sanchez-Mora et al., 2010; Smith, 2010; Yang et al., 2007). The children and adults of ADHD is also in dispute because a more most comprehensive meta-analysis was performed by Gizer et al. balanced gender distribution can be found in adult samples (2009), which investigated 38 markers within 18 genes and (Biederman et al., 1994), but the potential causes are still unclear. identified significant associations between several candidate genes It is also well known that ADHD is one of the earliest diagnosed including DAT1, DRD4, DRD5, 5HTT, HTR1B, and SNAP25 and child- and treated psychiatric disorders in children (Biederman and hood ADHD. As the accumulation of genetic data, more meta- Faraone, 2005). More than 80% of the investigated studies were analyses would speed up to uncover more significant genes. performed in children or adolescents with the most commonly To describe general patterns of more than 300 CGASs stored in used age group of 5–16 years old. Follow-up studies have indicated ADHD gene, we explored their study design and common sample that ADHD symptoms persist into adulthood in the majority of features, including age, gender and race of samples. Among which, children with ADHD (Biederman et al., 1996; Faraone et al., 2002; nearly 60% were probed with family-based samples, and another Faraone and Biederman, 1998). However, adult ADHD has been 19% adopted both family-based and case-control designs in one largely ignored during the past years. In 2007, the International research. In recent years, studies with case-control samples have Multicentre Persistent ADHD CollaboraTion (IMpACT) was emerged in virtue of comparative convenience of sample collec- founded with the aim to perform and promote research into the tion. However, since allele frequencies vary between ethnic or genetics of persistent ADHD and thus generated many interesting geographic populations, the confounding effects of population results (Franke et al., 2010; Landaas et al., 2010; Sanchez-Mora et stratification may bring about false positive associations in a al., 2011; Sanchez-Mora et al., 2010). So far, clinical evidence has case-control study (Perez-Lezaun et al., 1997). On the contrary, demonstrated that less obvious symptoms of hyperactivity or family-based design is more resistant to slightly variable popula- impulsivity and more inattentive symptoms, as well as more tion by testing transmission disequilibrium among families (Laird prevalent psychiatric comorbidity, were presented in persistent and Lange, 2006). The sample size distribution of studies using ADHD than childhood ADHD (Haavik et al., 2010). Many studies 14 Z. Li et al. / Psychiatry Research 219 (2014) 10–24 have been conducted to investigate common and distinct genetic (Lasky-Su et al., 2008a) or other specific phenotypes (Mick et al., risk factors which were responsible for persistent ADHD versus 2011), have been published. Among them, two studies were childhood ADHD (Barkley et al., 2006; Franke et al., 2012; Franke processed within the same sample collected as part of the et al., 2008; Franke et al., 2010). Ribases and his colleagues focused International Multi-Center ADHD Gene project (IMAGE). The on the association of shared and differential genetic variants with summary of ADHD GWASs is presented in Table 2. adult and childhood ADHD, and identified common susceptibility The first GWAS for ADHD (Lesch et al., 2008) was conducted factors, such as DDC (Ribases et al., 2009b), 5HT2A (Ribases with pooled DNA in adult ADHD. The sample used in this study et al., 2009b), CNTFR (Ribases et al., 2008) and SYT2 (Sanchez- was composed of 343 in-patients and out-patients and a total of Mora et al., 2013a), involved in both age groups. Meanwhile, they 304 control subjects. Even though no global significance was also reported childhood-specific contributions of NTF3 (Ribases et achieved, they identified several novel risk genes with association al., 2008), NTRK2 (Ribases et al., 2008) and DRD1 (Ribases et al., degree of Po1.0 10 6 and revealed remarkable overlap with 2012), as well as the participation of BAIAP2 (Ribases et al., 2009a) findings from GWAS in substance use disorders. The findings in in the continuity of ADHD across life span. this study support a common effect of genes coding for cell In addition, it has been widely investigated in various races/ adhesion molecules (e.g., CDH13 and ASTN2) and regulators of ethnicities all over the world for susceptibility genes of ADHD. As synaptic plasticity (e.g., CTNNA2 and KALRN). This study is the only population stratification plays a key role in genetic association GWAS in ADHD using adult patients and pooling strategy, while studies (Price et al., 2006), information about sample ethnicities the other seven ADHD GWASs recruited children/adolescents was also an important issue. According to our statistics on patients and their families or healthy controls as samples. The candidate gene association studies of ADHD, more than 60% were second ADHD GWAS (Neale et al., 2008) was carried out in 909 carried out in Caucasians, secondly in Mongoloids mainly focusing trios, and 438,784 SNPs were analyzed based on the Genetic on Chinese and Korean. Inconsistent results between the same Association Information Network (GAIN)/IMAGE dataset. However, locus and different ethnicities were often found in the candidate no genome-wide significant SNPs were found in this initial scan. gene association studies. For example, the COMT Val158Met SNP A subsequent study (Lasky-Su et al., 2008b) was conducted based (rs4680, G:A), was found significantly associated with ADHD, with on the same sample in order to identify novel susceptibility genes the over-transmission of A allele (Met) in a study carried out in by using six quantitative phenotypes generated from 18 ADHD 166 clinically referred, unrelated German children (Palmason et al., symptoms and finally detected two SNPs, rs6565113 and rs552655, 2010). However, this locus showed no evidence for a difference in in intronic regions of CDH13 and GFOD1 respectively with genome- allele distribution or genotype frequency between 340 Chinese wide significance. In 2010, Neale B.M. et al. (Neale et al., 2010a) ADHD probands and 226 controls (Qian et al., 2007). Some of the conducted another GWAS for ADHD in a sample with 896 cases inconsistencies in detecting the genetic markers of ADHD among and 2455 healthy controls of European ancestry, but still did not various ethnic populations might be attributed to differences in found any genome-wide significant associations. The situation of allele frequencies (Ji et al., 2013). The differential population no signal reaching the threshold for genome-wide statistical histories due to natural selection on regional populations may significance also happened to another multisite GWAS (Mick also lead to genetic heterogeneity of susceptibility to psychiatric et al., 2010) using 735 trios from 732 families. However, in this disorders (Li et al., 2013). To address this question, more compara- study, they also performed gene-based tests and found additional tive studies should be conducted among different ethnicities. evidence of association with SLC9A9, which is a candidate gene of interest for ADHD. Hinney A. and colleagues also performed a GWAS (Hinney et al., 2011) based on 495 German young patients 2.3. Genome-wide association studies with ADHD and 1300 population-based adult controls, but still no significant result was found. Currently eight genome-wide association studies for ADHD, Recently, Stergiakouli E. and his team (Stergiakouli et al., 2012a) which aims to identify the genetic factors associated with undertook a GWAS in 727 children with ADHD and 5081 compar- ADHD rather than drug response (Mick et al., 2008), time of onset ison subjects. Although no SNP achieved genome-wide significance

Table 2 Genome-wide association studies of ADHD (including meta-analysis).

No Study Study design Sample size No. of investigated Reported gene(s)b SNPsa

1 Lesch et al. (2008) Case-control 343 cases, 304 controls 504,219 SNPs (pooled) GPC6, MOBP, C9orf98, ITGA11, ITGAE, ASTN2, MGC33657, CSMD2, AK094352, ATP2C2, 2 Neale et al. (2008) Family-based 958 trios 438,784 SNPs NS c 3 Lasky-Su et al. (2008b) Family-based 958 trios 429,981 SNPs FLJ34870, HAS3, CLYBL 4 Mick et al. (2010) Family-based 735 trios 835,136 SNPs EMP2, C21orf34, CCDC46, ATPBD4, BMPR1B, UGT1A9, LOC389365, SLC9A9, ELOVL6, LOC643308 5 Neale et al. (2010a) Case-control 1150 cases and 2653 controls 1,033,244 SNPs NS (imputed) 6 Hinney et al. (2011) Case-control and family- 495 cases and 1300 controls 487,484 SNPs GRM5, BCL11A based 7 Stergiakouli et al. Case-control 799 cases and 6000 controls 502,702 SNPs NS (2012a) 8 Yang et al. (2013) Case-control 1040 cases and 963 controls 656,051 SNPs NCL, TMX3, ARSB, GRIK4 9 Neale et al. (2010b) Meta d 2064 trios, 896 cases, 2455 1,206,462 SNPs SHFM1, CHMP7, TNFRSF10D, TNFRSF10A, LOXL2, controls (imputed) TCEB1

a No. of investiated SNPs indicates SNPs passing quality control in this study. b Contents in this column are from the Catalog of Published Genome-Wide Association Studies (http://www.genome.gov/gwastudies/). c NS means no significant result was found and no eligible gene was reported in this study. d Meta-analysis of genome-wide association studies. Z. Li et al. / Psychiatry Research 219 (2014) 10–24 15 level in this study, the pathway analysis showed that thirteen The first report of structural variants in ADHD (Elia et al., 2010) biological pathways enriched for SNP association significantly was conducted in a sample of 335 ADHD patients and their overlapped with those enriched for rare CNVs, which means both parents, as well as 2026 unrelated healthy controls. After a common and rare genetic variants appear to be relevant to ADHD genome-wide genotyping and CNV detection, ADHD patients and and index-shared biological pathways. The first GWAS in Han the healthy controls showed comparable overall frequencies, and Chinese population has been conducted by Yang et al. (2013) in a no difference was seen in CNV size between cases and control. large sample consisting of 1040 cases and 963 controls. Although However, 222 rare inherited CNVs were found only in cases. These no single SNP achieved genome-wide significance, association of rare CNVs associated genes were found similar with candidate an increased burden of rare CNVs and a polygenic SNP component genes for autism, schizophrenia and Tourette syndrome, and was detected. Meanwhile, pathway analysis implicated several enriched in pathways demonstrating psychological and neurolo- cellular components, including neuron projections gical functions. The second genome-wide CNV analysis (Williams and synaptic components. To improve the power of GWASs, a et al., 2010) was undertook in 410 children with ADHD and 1156 meta-analysis was conducted in a total sample of 2064 trios, 896 unrelated ethnically matched controls. In this study, the authors cases and 2455 controls (Neale et al., 2010b), but it did not get assessed the genome-wide burden of large (4500 kb), rare (o1% significant associations either. Franke et al. (2009) discussed four population frequency) CNVs, and found increased rate of CNVs in GWASs published before 2009 and their most important findings. ADHD (0.156 vs 0.075; p¼8.9 10( 5)). The third genome-wide They described no genome-wide significant results and very CNV study (Lesch et al., 2011) was carried out in a cohort of 99 limited overlap among these original studies, except for an ambig- children and adolescents with severe ADHD. A total of 17 poten- uous association with CDH13 which has been reported in three tially syndrome-associated CNVs composed of four deletions and GWASs (Lasky-Su et al., 2008b; Lesch et al., 2008; Neale et al., 13 duplications with approximate sizes ranging from 110 kb to 2010a), as well as in the meta-analysis of seven genome-wide 3 Mb were identified. Among them, two CNVs occurred as de novo linkage studies (Zhou et al., 2008). Furthermore, to integrate the and nine were inherited from a parent with ADHD, whereas five findings from GWAS for better understanding of their functions are transmitted by an unaffected parent. In this study, additional and deduce new knowledge, Poelmans et al. (2011) conducted investigation of gene NPY (neuropeptide Y) was also performed network analysis for 85 genes from five GWASs top SNPs and since it was included in a 3 Mb duplication on chromosome identified a neurodevelopmental network for ADHD. The analysis 7p15.2–15.3, and result showed a nominally significant association would promote our understanding of the molecular basis of the of this duplication with increased NPY plasma concentrations. All disorder. of these findings implicate that both frequent and rare variants Considering the complex heterogeneity of ADHD, a larger influence the development of this common multi-factorial syn- sample might be useful to get a significant association signal. drome. After that, Lionel et al. (2011) also identified 23 de novo and Besides, through a comparison with data on other disorders, such rare CNVs in 248 unrelated ADHD patients using million-feature as schizophrenia, , autism and depression, within genotyping arrays. They also explored the overlap of CNV risks in Psychiatric GWAS Consortium (PGC), it is suggested that genome- ADHD and autism using the same microarrays to test for rare CNVs wide significance can only be achieved upon a sample size of in an independent, newly collected cohort of 349 unrelated 12,000 individuals including both cases and controls for psychiatry individuals with a primary diagnosis of autism. In the end, results diseases (Fliers et al., 2012). To extend the scope of ADHD GWAS, not only provided support for a role of rare CNVs in ADHD risk but an international collaboration should be enhanced to make a also reinforced evidence for the existence of common underlying larger sample. susceptibility genes for ADHD, autism, and other neuropsychiatric disorders. 2.4. Copy number variation studies Recently, six genome-wide CNV studies for ADHD have been published showing that structure variant is attracting more attention There have been ten articles describing CNV research in ADHD for its contribution to both children and adult ADHD. In one of these to verify the hypothesis that individually rare and inherited researches (Elia et al., 2012), the authors performed a whole-genome structural variants might contribute to disease risk (Antshel et CNV study on 1013 ADHD cases and 4105 healthy children of European al., 2006). Among which, eight studies were conducted in Cauca- ancestry. They also evaluated statistically significant findings in multi- sians and only one study was undertook in Han Chinese, except for ple independent cohorts with a total of 2493 cases and 9222 controls one study in mixed samples. The summary of ADHD CNVs is using matched platforms. With advantage of large sample, this study presented in Table 3. detected the association of metabotropic glutamate receptor gene

Table 3 Genome-wide CNV Analyses of ADHD.

No. Study Design Ethnicity Sample size No. of reported No. of de CNVsa novo CNVs

1 Elia et al. (2010) Case-control and family-based Caucasian 335 trios and 2026 controls 222 N/Ab 2 Lesch et al. (2011) Case-control and family-based Caucasian 99 case and 100 control 17 2 3 Williams et al. (2010) Case-control Caucasian 410 cases and 1156 unrelated 57 6 controls from the 1958 British Birth Cohort 4 Elia et al. (2012) Case-control Caucasian 1013 cases and 4105 healthy controls 19 12 5 Jarick et al. (2012) Case-control Caucasian 489 cases and 1285 controls 50 N/A 6 Lionel et al. (2011) Case-control MIX 248 probands and 2357 controls 23 4 7 Stergiakouli et al. (2012b) Case-control Caucasian 799 cases and 6000 controls 0 0 8 Williams et al. (2012) Case-control Caucasian 896 cases and 2455 controls 460 N/A 9 Ramos-Quiroga et al. (2014) Case-control Caucasian 400 cases and 526 controls 367 N/A 10 Yang et al. (2013) Case-control Chinese 1040 cases and 963 controls 6 N/A

a No. of reported CNVs indicates those CNVs identified in patients only. b N/A means no de novo CNVs were reported in the study. 16 Z. Li et al. / Psychiatry Research 219 (2014) 10–24 networks with ADHD on the basis of the observation that CNVs understanding and usage of these data, here we systematically affecting metabotropic glutamate receptor genes were enriched across reviewed these genes from three aspects. all cohorts (P-value¼2.1 10 9). In addition, comparing with the identification of general rare CNVs in previous studies, Williams et al. 3.1. Hot genes (2012) confirmed the duplications at 15q13.3 as a novel risk factor for ADHD by performing a genome-wide analysis of large, rare CNVs We firstly investigated overall status of molecular genetic (o1% population frequency) in a sample composed of 896 children studies for ADHD and defined the genes which have been reported with ADHD and 2455 healthy comparison subjects from the IMAGE II by at least five association studies as “hot genes”. There are 24 “hot Consortium. They firstly identified gene CHRNA7 at chromosome genes” following this rule (Table 4), and they represent top 7% of 15q13.3 in single-locus analysis and then validated its association with ADHD candidate genes according to the number of studies they ADHD in an additional 2242 ADHD cases and 8552 controls from four were reported. Most of these genes are involved in biological independent cohorts. Besides, they also confirmed previous findings process related to monoamine neurotransmitter, including mono- about common CNVs between ADHD and autism and schizophrenia. amine metabolic biosynthesis and monoamine transmission In another whole-genome CNV analysis (Jarick et al., 2012), the (transporter and receptor). These results are consistent with the authors identified another significantly associated CNV region harbor- hypothesis indicated by pharmacologic, neuroimaging and animal- ing gene PARK2 which is known to be associated with Parkinson model studies that the imbalance of dopaminergic, serotonergic disease. This CNV study was conducted based on 489 young ADHD and noradrenergic neurotransmission may contribute to or exacer- patients and 1285 adult population-based controls. Besides, another bate ADHD (Sharp et al., 2009). CNV study of ADHD combined results from GWAS and genome-wide Among the investigated genes, SLC6A3 and DRD4 have been CNVs experiments (Stergiakouli et al., 2012b) as mentioned above. It extensively studied in more than 60 studies; genes within the focused on examining whether associated SNPs, including those below same families with them also accumulated more evidences than conventional levels of significance, influencedthesamebiological others, like DRD1, DRD2, DRD3, DRD5 SLC6A4 and SLC6A2. Other pathways affected by CNVs and got positive results. This is the first neurotransmitter transporters, such as receptors HTR1B, study to investigate the common genetic mechanism represented by HTR2A and HTR2C, adrenergic receptors ADRA2A and ADRA2C, both common SNPs and rare CNVs. In addition, the first genome-wide cholinergic receptor CHRNA4 were also in the list of “hot genes”. association study of both common and rare variants in a large Han Besides, genes involved in the process of , Chinese sample of 1040 cases and 963 controls showed a significantly and other were highlighted in the higher rate of rare CNVs (1.875% vs. 1.830%, ratio: 1.02, P-value¼0.038) “hot genes” list as well, including COMT, DBH, MAOA and MAOB, and proportion of individuals carrying rare CNVs (55.8% vs. 51.2%, TPH1 and TPH2, TH, and DDC. It has been well known that tyrosine ratio: 1.09, P-value¼0.026) for the ADHD group than for controls and tryptophan are important neurotransmitter precursors and in (Yang et al., 2013). Besides, to explore the structure variants in adult connection with mood disorder (Shaw et al., 1979), which imply ADHD, the first genome-wide CNV study on adults was performed in the roles of above in neurological function. In addition, 400 patients and 526 controls (Ramos-Quiroga et al., 2014). The genes related to neurodevelopment and neuroplasticity, like BDNF authors identified a highly significant excess of insertions in ADHD (Aureli et al., 2010; Cho et al., 2010; Kent et al., 2005; Lanktree et patients compared to controls (64% versus 48%, 1.33-fold, P- al., 2008; Lee et al., 2007; Oades et al., 2008; Ribases et al., 2008; value¼2.4 10 3), which is in accordance with previous reports in Xu et al., 2007) and SNAP25 (Barr et al., 2000; Brookes et al., 2006; children with ADHD or in other psychiatric disorders (Williams et al., Brophy et al., 2002; Choi et al., 2007; Feng et al., 2005; Gizer et al., 2010, 2012). After stratification by CNV size, a significant excess only 2009; Guan et al., 2009; Kim et al., 2007; Kustanovich et al., 2003; showed in small CNVs (from 100 kb to 500 kb; 1.35-fold; P- Mill et al., 2002, 2004; Sarkar et al., 2012; Zhang et al., 2011), have value¼1.3 10 3). These differences still remain significant for con- also been widely investigated and many evidences for their sideration of CNVs that overlap genes or evaluation of structure association with ADHD have been accumulated. BDNF encodes a variants spanning candidate genes for psychiatric disorders (duplica- of the nerve growth factor family, which is induced by tions, 1.41-fold, P-value¼0.024 and 2.85-fold, P-value¼8.5 10 3 cortical neurons and is necessary for survival of striatal neurons in respectively). The study also investigated whether the genomic varia- the brain (Autry and Monteggia, 2012). Results from pharmacolo- tion in their adult cohort is enriched for CNVs previously identified in gical experiments and animal models also support its association children with ADHD, but no significant evidence was detected. The with ADHD (Chase et al., 2007; Chourbaji et al., 2004; Meredith et results supported that the persistent ADHD throughout the lifespan al., 2002). Another hot candidate gene SNAP25 was also examined might be contributed by a specific genetic background (Biederman et in more than ten studies. The product of gene SNAP25 is a pre- al., 1995; Ribases et al., 2009a; Ribases et al., 2008, 2009b). synaptic plasma membrane protein involved in the regulation of Although several de novo and rare CNVs were identified and neurotransmitter release (Sollner et al., 1993). Evidences from specific loci with statistically significant association were found, animal models also suggest it as a candidate gene for ADHD the way these CNVs taking effect is still unclear. Besides, genes (Hess et al., 1996). associated with reported CNVs hardly have connection with genes Although as “hot genes”, both positive and negative findings demonstrated by candidate gene association studies or GWASs. were reported for each of them and 10 out of 24 “hot genes” There is still a long way to detect structure variations associated owned more negative results than positive ones. More replication with ADHD, and results from different kind of genetic studies studies, as well as meta-analyses should be conducted to tell the should be integrated to make a full presentation of genetics true and specific association of these “hot genes” with ADHD. of ADHD. 3.2. Multi-evidence supported genes

3. Evaluation of candidate genes for ADHD Association between genes and phenotypes can be tested through several ways including linkage study, GWAS, candidate Although more than 300 candidate genes have been proposed gene association study and CNV research, and thus there is an to be related to the susceptibility or etiology of ADHD, more than intuitive assumption that genes obtaining more than one type of 70% of these genes were reported only once in one single study. To evidence are more convincing to be associated with ADHD. evaluate these candidate genes and provide insights for better Following this train of thought, we summarized 359 published Z. Li et al. / Psychiatry Research 219 (2014) 10–24 17

Table 4 Summary of high-confidence candidate genes for ADHD which are composed by “hot genes” (No. of studies4 ¼5), “multi-evidence supported genes”, and “prioritized genes”.

Gene symbol Location Gene name No. of No. of studies b Tag of gene(s) investigated markers a Hot genes Multi-evidence c Prioritized genes d

SLC6A3 5p15.3 Solute carrier family 6 19 70(43/1/26) Y CGAS, linkage T (neurotransmitter transporter), member 3 DRD4 11p15.5 receptor D4 9 67(49/0/18) Y T COMT 22q11.21 Catechol-O-methyltransferase 10 29(7/0/22) Y CGAS, CNV SLC6A4 17q11.2 Solute carrier family 6 5 26(13/0/13) Y P (neurotransmitter transporter), member 4 DRD5 4p16.1 D5 7 22(14/2/6) Y SNAP25 20p12-p11.2 Synaptosomal-associated protein, 34 21(16/0/5) Y T 25 kDa DBH 9q34 Dopamine beta-hydroxylase (dopamine 21 21(12/0/9) Y P beta-) MAOA Xp11.4-p11.3 A 18 20(13/0/7) Y T SLC6A2 16q12.2 Solute carrier family 6 52 16(10/1/5) Y T (neurotransmitter transporter), member 2 BDNF 11p14.1 Brain-derived neurotrophic factor 8 16(8/0/8) Y HTR1B 6q13 5-Hydroxytryptamine (serotonin) 4 14(5/0/9) Y P receptor 1B, G protein-coupled HTR2A 13q14-q21 5-Hydroxytryptamine (serotonin) 4 13(7/0/6) Y P receptor 2 A, G protein-coupled ADRA2A 10q25.2 Adrenoceptor alpha 2 A 4 13(4/0/9) Y TPH2 12q15 2 8 11(8/0/3) Y T DRD2 11q22-q23 4 10(3/0/7) Y CGAS, linkage P DRD1 5q34-q35 9 8(5/0/3) Y DRD3 3q13.3 2 8(1/0/7) Y P CHRNA4 20q13.33 Cholinergic receptor, nicotinic, alpha 4 4 7(4/0/3) Y T (neuronal) ADRA2C 4p16.3 Adrenoceptor alpha 2C 3 7(2/1/4) Y TH 11p15.5 2 7(2/0/5) Y P DDC 7p12.1 Dopa decarboxylase (aromatic L-amino 3 6(5/0/1) Y T acid decarboxylase) MAOB Xp11.4-p11.3 3 6(2/0/4) Y TPH1 11p15.3-p14 Tryptophan hydroxylase 1 2 6(2/0/4) Y HTR2C Xq23 5-Hydroxytryptamine (serotonin) 3 5(2/0/3) Y P receptor 2C, G protein-coupled SYP Xp11.23- Synaptophysin 3 4(4/0/0) T p11.22 LPHN3 4q13.1 Latrophilin 3 7 4(3/1/0) CGAS, linkage SYT1 12q21.2 Synaptotagmin I 2 4(2/0/2) P CDH13 16q23.3 Cadherin 13 7 4(1/1/2) Linkage, GWAS, CNV GRIN2A 16p13.2 Glutamate receptor, ionotropic, 5 4(1/0/3) CGAS, linkage N-methyl D-aspartate 2A FADS2 11q12.2 2 4 3(3/0/0) CGAS, linkage T GRM7 3p26-p25 Glutamate receptor, metabotropic 7 2 3(2/0/1) CGAS, CNV PNMT 17q Phenylethanolamine 3 3(2/0/1) T N-methyltransferase STX1A 7q11.2 Syntaxin 1A (brain) 4 3(2/0/1) P HTR3B 11q23.1 5-Hydroxytryptamine (serotonin) 2 3(1/0/2) CGAS, linkage receptor 3B, ionotropic HTR1A 5q11.2-q13 5-Hydroxytryptamine (serotonin) 5 2(2/0/0) P receptor 1A, G protein-coupled HTR1E 6q14-q15 5-Hydroxytryptamine (serotonin) 2 2(2/0/0) T receptor 1E, G protein-coupled SLC9A9 3q23-q24 Solute carrier family 9, subfamily A 25 2(2/0/0) CGAS, GWAS T (NHE9, cation proton antiporter 9), member 9 CPLX2 5q35.2 Complexin 2 2 2(1/1/0) CGAS, CNV GRM5 11q14.3 Glutamate receptor, metabotropic 5 1 2(1/1/0) Linkage, GWAS, CNV ADRA1B 5q33.3 Adrenoceptor alpha 1B 11 2(1/0/1) CGAS, linkage ADRB2 5q31-q32 Adrenoceptor beta 2, surface 1 2(1/0/1) P CALY 10q26.3 Calcyon neuron-specific vesicular 5 2(1/0/1) CGAS, CNV protein FTO 16q12.2 Fat mass and obesity associated 2 2(1/0/1) CGAS, CNV GDNF 5p13.1-p12 Glial cell derived neurotrophic factor 12 2(1/0/1) CGAS, linkage SLC1A3 5p13 Solute carrier family 1 (glial high 20 2(1/0/1) CGAS, linkage affinity glutamate transporter), member 3 ASTN2 9q33 Astrotactin 2 N/A 2(0/2/0) Linkage, GWAS EMP2 16p13.2 Epithelial membrane protein 2 N/A 2(0/2/0) Linkage, GWAS 18 Z. Li et al. / Psychiatry Research 219 (2014) 10–24

Table 4 (continued )

Gene symbol Location Gene name No. of No. of studies b Tag of gene(s) investigated markers a Hot genes Multi-evidence c Prioritized genes d

ATP2C2 16q24.1 ATPase, Caþþ transporting, type 2C, 1 2(0/1/1) Linkage, GWAS, CNV member 2 CHRNA7 15q13.3 Cholinergic receptor, nicotinic, alpha 7 3 2(0/1/1) Linkage, CNV P (neuronal) PRKG1 10q11.2 Protein kinase, cGMP-dependent, type I 1 2(0/1/1) GWAS, CNV ADRB1 10q25.3 Adrenoceptor beta 1 2 2(0/0/2) P SLC18A2 10q25 Solute carrier family 18 (vesicular 1 2(0/0/2) P monoamine transporter), member 2 VAMP2 17p13.1 Vesicle-associated membrane protein 2 6 2(0/0/2) P (synaptobrevin 2) ARVCF 22q11.21 Armadillo repeat gene deleted in 8 1(1/0/0) CGAS, CNV velocardiofacial syndrome BCHE 3q26.1-q26.2 12 1(1/0/0) CGAS, CNV CCSER1 4q22.1 Coiled-coil serine-rich protein 1 4 1(1/0/0) CGAS, CNV CNTF 11q12 Ciliary neurotrophic factor 1 1(1/0/0) CGAS, linkage CPLX4 18q21.32 Complexin 4 2 1(1/0/0) CGAS, linkage DIRAS2 9q22.32 DIRAS family, GTP-binding RAS-like 2 12 1(1/0/0) CGAS, linkage GPRC5B 16p12 G protein-coupled receptor, class C, 1 1(1/0/0) CGAS, linkage group 5, member B HES1 3q28-q29 Hes family bHLH transcription factor 1 1 1(1/0/0) CGAS, CNV NOS1 12q24.22 1 (neuronal) 1 1(1/0/0) CGAS, GWAS SPOCK3 4q32.3 Sparc/osteonectin, cwcv and kazal-like 40 1(1/0/0) CGAS, CNV domains proteoglycan (testican) 3 DNM1 9q34 Dynamin 1 N/A 1(0/1/0) P IL20RA 6q23.3 Interleukin 20 receptor, alpha 1 1(0/1/0) Linkage, GWAS MMP7 11q21-q22 Matrix metallopeptidase 7 (matrilysin, 1 1(0/1/0) Linkage, GWAS uterine) TCERG1L 10q26.3 Transcription elongation regulator N/A 1(0/1/0) GWAS, CNV 1-like TRIO 5p14-p15.1 Trio Rho guanine nucleotide exchange 1 1(0/1/0) Linkage, GWAS factor CHRNA3 15q24 Cholinergic receptor, nicotinic, alpha 3 1 1(0/0/1) P (neuronal) HTR3A 11q23.1-q23.2 5-Hydroxytryptamine (serotonin) 2 1(0/0/1) P receptor 3 A, ionotropic

a The investigated markers indicate SNPs and other variants (including VNTR, microsatellite, STR, duplication, SNP without rs ID etc.) tested within the gene. If the gene has been investigated in more than one study, the No. of investigated markers denotes the sum of investigated markers in all studies. If the gene is merely reported by GWAS, linkage study or CNV study, the No. of investigated markers is set as ‘N/A’. b Studies count are from ADHD gene. The numbers are No. of studies (No. of studies with significant results/No. of studies with trend results/No. of studies with non- significant). c “Multi-evidence supported genes” mean ADHD associated genes indicated by more than one study type, which comprise (1) genes reported by candidate gene association study (denoted by CGAS), (2) genes reported by GWAS or mapped by significant/trend GWAS SNPs (denoted by GWAS), (3) genes mapped by significant regions (denoted by linkage) and (4) genes mapped by CNVs (denoted by CNV). d “T” means training gene and “P” means high-prioritization gene.

ADHD genes and generated four gene lists with various evidences most of candidate genes were from hypothesis and existing including: (1) genes supported by candidate gene association knowledge so that novel genes from other study types did not studies with significant associations; (2) genes reported by GWAS draw much attention. It reminds that more attention should be or mapped by significant/trend GWAS SNPs; (3) genes mapped by paid on novel genes with multi-evidence support. It also hints that significant regions and (4) genes mapped by CNVs. We then cross-validation studies, as well as convergence and integration performed an intersection analysis on above four lists and those analysis should be promoted to build the interconnection of genes existing in more than one list were regarded as “multi- different types of genetic factors (Gilman et al., 2012). evidence supported genes”. By this means, we picked up 36 “multi-evidence supported genes” as shown in Table 4. 3.3. Prioritized genes As observed, no gene had obtained positive supports from all types of evidence. Three genes (CDH13, ATP2C2 and GRM5)were Gene prioritization is an effective method to pick up the most supported by three types of evidence and others were supported promising genes from a large pool of candidate genes in recent by duple-evidence. Of which, LPHN3, a gene recently described to years (Tranchevent et al., 2010). To further evaluate candidate have a high potential for the prevention and treatment of ADHD genes from literature, we conducted gene prioritization analysis (Arcos-Burgos and Muenke, 2010), deserves more attention since for the 359 literature-origin candidate genes of ADHD as what we many solid works, including evidences from linkage analysis, have done for more than 3000 candidate genes from both CGAS, brain imaging studies (Arcos-Burgos et al., 2010a; Ribases literature and extended analyses in ADHD gene (Chang et al., et al., 2011), neural activity (Fallgatter et al., 2013) and animal 2012). The methodology has been described in detail in models (Wallis et al., 2012), have sustained its involvement in the Supplementary materials. By adopting five difference multiple- disorder. It is worth mentioning that all three genes with triple- source based gene prioritization tools, i.e. Endeavour (Aerts et al., evidence were supported by GWAS, linkage and CNV study types, 2006; Tranchevent et al., 2008), DIR (Y. Chen et al., 2011), but not candidate gene association study. It may reflect one of the ToppGene (Chen et al., 2009), ToppNet (Chen et al., 2009) and drawbacks of previous candidate gene association studies that TargetMine (Y.A. Chen et al., 2011), we obtained 32 genes with Z. Li et al. / Psychiatry Research 219 (2014) 10–24 19 high priority, shown as “prioritized genes” in Table 4. Except for PET/SPECT) (Durston, 2010), and more efforts will be needed to transporters/receptors for neurotransmitters and enzymes func- make imaging genetics for ADHD prosperous and fruitful. In tioning in amino acid metabolism, genes involved in nervous addition, the genetic studies reviewed here were mainly focused system development, especially in synapse structure and function, on identifying genetic susceptibility factors of ADHD in diagnosed were highlighted in the prioritized results, such as SNAP25, SYP, patients. However, other ADHD symptom measures or drug SYT1, STX1A and VAMP2 genes. It has been known that STX1A, responses could also be considered as phenotypes to test the VAMP2 and SNAP25 form a complex as core SNARE proteins to associated genes, and the result would facilitate the understanding contribute pre- and postsynaptic exocytosis (Kennedy and Ehlers, of the gene function in the disease. For example, the study 2011), and the dysfunction of the complex may be one of the conducted by Bralten et al. (2013) used several quantitative ADHD determinants of disease pathogenesis (Corradini et al., 2009). It measures as phenotype. Meanwhile, pharmacogenetics has always also reminds that more attention should be paid on synapse been an important issue in ADHD. Several specific genes have been related genes to find out the function mechanism of ADHD and reported to be involved in the response to methylphenidate perhaps potential targets of novel drug for ADHD. (Contini et al., 2013), atomoxetin (Polanczyk et al., 2010) etc. In summary, the total 70 candidate genes of ADHD with more Among the specific genes, SLC6A3 and DRD4 are the most well supporting evidences for further verification study were generated studied ones (Froehlich et al., 2010). Additional genes significantly from “hot genes”, “multi-evidence supported genes” and “prior- associated with medication response include ADRA2A itized genes” lists, as presented in Table 4. Among them, DRD2 and (Polanczyk et al., 2007b), COMT (Mattay et al., 2003), DRD5 (Tahir SLC6A3 were covered by three classes, and 18 genes were covered et al., 2000), SLC6A2 (Kooij et al., 2008) and SNAP25 (McGough et by two of them, such as gene COMT was classified as “hot genes” al., 2006). Lastly, the enrichment of various types of genetic data and “multi-evidence supported genes”, three genes (CHRNA7, calls for cross validation, convergent and integration analyses as in SLC9A9 and FADS2) were classified as “prioritized genes” and other psychiatric disorders (Ayalew et al., 2012; Gilman et al., “multi-evidence supported genes”, and 14 genes (DBH, HTR1B, 2012). Accordingly, more powerful statistical methods and inte- HTR2C, TH, DRD4, SLC6A4, MAOA, SNAP25, SLC6A2, HTR2A, TPH2, grative analysis tools will be needed to facilitate the research, by DRD3, CHRNA4 and DDC) were classified as “hot genes” and which it is possible to conduct more effective and powerful in- “prioritized genes”. It is also worth mentioning that some depth data analyses for proposing more reliable clues for the “multi-evidence supported genes” and “prioritized genes” we discovery of genetic mechanisms of ADHD. obtained in this article did not receive much attention in previous research, like genes HTR3A and CHRNA3 (Ribases et al., 2009b; Thakur et al., 2012). These genes were previously under-estimated, Acknowledgments but they are worthy of future investigation. This work was supported by the Partnership Program for Creative Research Teams of Chinese Academy of Sciences and State 4. Conclusion Administration of Foreign Experts Affairs (Y2CX131003), the Knowledge Innovation Program of the Chinese Academy of This article reviewed and explored the current molecular genetic Sciences (KSCX2-EW-J-8), the Strategic Priority Research Program studies of ADHD from three aspects: (1) the main achievements (B) of the Chinese Academy of Sciences (XDB02030002) and Key from various molecular genetic studies of ADHD were summarized; Laboratory of Mental Health, Institute of Psychology, Chinese (2) an additional description of general patterns of study design and Academy of Sciences. common sample features were reviewed and presented; (3) candi- date ADHD genes were systematically evaluated. Through a com- Appendix A. Supporting materials prehensive review beyond literal summary of general results, we present here the main studies and genetic factors discovered before Supplementary data associated with this article can be found in to give a better summary of molecular genetic studies of ADHD. theonlineversionathttp://dx.doi.org/10.1016/j.psychres.2014.05.005. Besides, the features of these investigated studies were demon- strated to provide scientific guidance for the future study design. Furthermore, comparison and evaluation of reported genes were References performed, which would provide evidence and clues for further replication study, which helps extend our knowledge about the Adams, J., Crosbie, J., Wigg, K., Ickowicz, A., Pathare, T., Roberts, W., Malone, M., Schachar, R., Tannock, R., Kennedy, J.L., Barr, C.L., 2004. 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