Genetic Studies of Autism Spectrum Disorder in Asians

Home , DLX6, GABRB3, GRIK2, Tetrasomy, Tetrasomy 9p

Overview Taiwanese Journal of Psychiatry (Taipei) Vol. 29 No. 3 2015 • 139 •

Luke Y. Tsai, M.D.*

The genetics of autism spectrum disorder (ASD) has been studied for more than three decades. Earlier twin and family studies have provided some support for a genetic rȏle in the development of ASD. More recent molecular techniques have identifi ed more than 400 potential genes involved in etiology of ASD. But many of the genes have also been identifi ed as potential genes for other neuropsychiatric disorders. The fi eld of ASD genetics has concluded that ASD as defi ned for the last three decades is a heterogeneous clinical disorder with heterogeneous genetic etiologies. This overview is to focus on the ethnic differences as a potential factor of the heterogeneous etiologies. In this overview, the author attempts to compile all available published ASD genetic studies in Asian populations to explore the direc- tions for future comparisons between Asian and Western ASD genetic studies. It is concluded that the quantity of the Asian ASD genetic studies is still quite limited, though there are a few studies indeed have found some ethnic differences in certain candidate genes for ASD.

Key words: candidate gene, genome wide, copy number variation, ethnic difference (Taiwanese Journal of Psychiatry [Taipei] 2015; 29: 139-54)

infantile autism in almost 400 siblings of autistic Introduction individuals in the literature. However, the 7 (1.8%) undocumented cases of autism among sib- When Kanner (1943) ﬁ rst described infantile lings, did suggest a familial clustering of autism. autism, he suggested that it was resulted from an There were only 18 pairs of twins reported in the inborn defect of presumably constitutional origin literature before 1976. Hanson and Gottesman [1]. Over the next three decades, the possible rȏle (1976) concluded that the data were inadequate of genetic factors tended to be dismissed. In an for genetic analysis and there was no report on extensive review and analysis of the literature, offspring of autistic individuals. They concluded Hanson and Gottesman (1976) concluded that that the cause of infantile autism is unlikely to be there was no clear evidence exsits to indicate that genetic [2]. This conclusion is also supported by genetic factors play a rôle in infantile autism [2]. the lacking of identiﬁ ed chromosome anomalies They found no adequately documented cases of associated with infantile autism [3] and by the lit-

Departments of Psychiatry and Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, U.S.A. Received: October 2, 2015; accepted: October 7, 2015 *Corresponding author. No. 2385, Placid Way, Ann Arbor, 48105, Michigan, U.S.A. E-mail: Luke Y. Tsai • 140 • Autism Spectrum Disorder

erature review carried out by Smalley et al. (1988), showing only some 2% of cases with two autistic Search Strategy and children in the same family [4]. Identifi cation of Since then and over the last three decades, Relevant Studies considerable evidence has accumulated to support the thought that genetic factors may play a con- To identify the studies that support the ge- tributory hereditary rȏle in the devel-opment of netic role of the development of ASD, I conducted ASD in a subgroup of individuals with such a dis- a systematic literature search to locate the pub- order. Furthermore, the development of new tech- lished studies up to August 2015 that examined nologies in both molecular genetics and cytoge- the genetics of ASD in Chinese, Japanese and netics has substantially enhanced our capacity to Korean populations. The scope of the search was investigate the rôle of genetics in ASD. Attention limited to English-language journal articles. has turned to a more detailed consideration of spe- Publications were identifi ed by conducting cifi c aspects of genetic factors relating to the de- searches in the major scientifi c literature databas- velopment of ASD. es Pub-Med, MEDLINE, and PsycINFO. Search In this overview, I will focus on the genetic was also conducted by entering the following studies of ASD in Asian populations including terms: autism, autistic disorder, Asperger’s disor- ethnic Chinese, Japanese, and Koreans because der, PDD-NOS, pervasive developmental disor- some genetic studies have found “clear ethnic dif- der, autism spectrum disorder, gene, and genetics. ferences” in certain ASD related gene [e.g., gam- Key fi ndings and the bibliographies of many pre- ma-aminobutyric acid-A receptor subunit β3 vious reviews of genetics of ASD were incorpo- (GABRB3) gene [5], or confl icting results in dif- rated into the selection of studies. Reference lists ferent ethnic background [e.g., neuroligin 3 from relevant articles in recent editions of key (NLGN3) and neuroligin 4X (NLGN4X) genes [6]; journals likely to publish such genetic studies CD38 gene [7]. I hope that such a review would (e.g., Journal of Child Psychology and Psychiatry, build a database for future ASD genetic studies of Autism, Journal of Autism and Developmental comparisons between various ethnic groups to Disorders, Research of Autism Spectrum Disorder) help clarify the relevance of the genes to ASD. were also used to identify the relevant studies. Due to the limited space allowed for this overview paper, only the summaries of the identi- Twin Studies fi ed relevant studies are presented here. Readers of the Taiwanese Journal of Psychiatry are re- ‧ Ishijima and Kurita (2007) reported a pair of ferred to other related references for the details of Japanes MZ male twins concordant for DSM- the functions of the genes which are presented in IV Asperger’s disorder [8]. this paper. Family Studies

‧ To investigate the behavioral problems and parenting style among children with autism and their siblings in an ethnic Chinese population, Tsai LY • 141 •

Gau et al. (2010) recruited a total of 151 children with DSM-IV autistic disorder, aged 3-12 Cytogenetics and years, 134 siblings without autism, and 113 Chromosome Abnormalities normally developing controls. The investigators found that children with autism had signifi - Cytogenetics mainly investigates chromo- cantly more severe behavioral problems, and some abnormalities, such as translocation, inver- obtained less affection and more overprotection sion, deletion, and duplication. Studies of the loca- and authoritarian controlling from their parents tion of chromosomal abnormalities and breakpoints than the unaffected siblings. But compared to can be extremely useful in the identifi cation and the controls, unaffected siblings have shown mapping of genes predisposing to any monogenic some behavioral problems. The investigators or polygenic disease. To date, there have been suggested that the unaffected siblings may be at many reports in the literature of chromosome ab- risk for developing the wide range of behav- normalities in autism covering a broad spectrum of ioral problems and impaired parent–child inter- anomalies, including terminal and interstitial dele- actions as exhibited by their siblings with au- tions, balanced and unbalanced translocations and tism [9]. inversions. The following is the study summaries, reporting chromosomal abnormalities in Asian in- Studies of Personality Traits dividuals with ASD or autistic behaviors: and Behavioral Characteristics Chromosome 2 - Deletion: a patient with autistic behavior, at 2p15-16.1 [11]; a 3 years and 4 ‧ Shen et al. (2011) reported the clinical and ge- months old girl with autistic features, at 2q24.2- nomic characteristics of three 16p11.2 deletion q24.3 [12]. carriers in a Chinese family. The father carries Chromosome 4 - Deletion: an 8 years old boy a de novo 16p11.2 deletion, and it was transmit- with ASD at 4q35.1-35.2 [13]. ted to the proband and sib. The proband pre- Chromosome 8 - Deletion: a 12-year-old boy sented with ASD, intellectual disability, learn- with ASD at 8p23.2-pter [13]. ing diffi culty, congenital malformations such as Chromosome 9 - Mosaic tetrasomy 9p: A atrial septal defect and scoliosis. His dysmor- 20-year-old female patient with autism [14]. phic features include myopia and strabismus, Chromosome 18 - Duplication: A 7-year-old fl at and broad nasal bridge, etc. While the fa- girl with autism, at 18q12.1 [15]. ther shared same neurodevelopmental prob- Chromosome X - Deletion: 2 brothers with lems as the proband, the younger brother does autistic behavior, at Xp11.22 [16]; Duplication: a not show many of the proband’s phenotypes. female with ASD, in Xp11.22-p11.23 [17]; Fragile The authors comment that their study demon- X: 8 children with ASD [18]. strates the different developmental trajectory Sex chromosomeaneuploidy – 2 ASD cases and discordant phenotypes among family mem- with 47, XXY, one ASD case with 47, XYY [19]. bers with the same 16p11.2 deletion and further Reciprocal chromosomal translocation be- illustrates the phenotypic complexity and het- tween long arms of chromosomes 4 and 14, desig- erogeneity of the 16p11.2 deletion [10]. nated t(4;14)(q31.3;q24.1) - in a patient with Asperger’s disorder [19]. • 142 • Autism Spectrum Disorder

chromosomal abnormality; and has been located Candidate Genes positionally by linkage studies [22]. Over the last two decades, many candidate The fi rst molecular genetic studies of autism gene studies have been conducted, and more than took form in candidate gene association studies. 100 functional or positional candidate genes have The introduction of cost-effective resequencing been tested directly. The majority of them did not has made it possible to build on cytogenetic stud- reveal a conclusive evidence of involvement in ies and obtain evidence for the involvement of ASD by showing clear picture of either positive specifi c candidate genes in the ASDs. Candidate association at a certain gene or genomic locus or gene study is hypothesis-driven research which identifi cation of disease-relevant variations or choses several candidate genes for additional mutations. This might be the result of allelic het- study based on known involvement in pathways erogeneity, sample heterogeneity, small samples related to neurodevelopment and/or evidence sizes or ethnically distinct backgrounds [22]. from pharmacological interventions that implicate Nonetheless, several striking autism susceptibility specifi c biomolecular pathways [20]. Once candi- genes with high penetrance have been identifi ed. date genes have been identifi ed, affected individu- The following are the autism-linked genes that als and age-, gender-, and ethnically matched con- have been studied in Asian populations: trols are tested for the presence of mutations in the Neuroligin 3 (NLGN3) and 4 (NLGN4) [6 , gene sequence or relative levels of expressed pro- 23 - 25]; NRXN1 (neurexin 1) [26]; CNTNAP2 tein. Association studies use polymerase chain re- (contactin-associated protein-like 2) [27]; SHANK action to amplify putative candidate genes and (SH3 multiple ankyrin repeat domain protein) [28 search for mutations to determine whether a poly- - 30]; fatty acid-binding protein (FABP) gene [31, morphism (a change in the typical genetic se- 32]; NADH-ubiquinone oxidoreductase 1 alpha quence that may or may not be expressed as a subcomplex 5 (NDUFA5) gene [33]; MET (met re- functional mutation) within a gene shows a sig- ceptor tyrosine kinase) gene [34]; REELIN nifi cant association with the disease [21]. (RELN) gene [35-37]; ATP2B2 (ATPase, calcium- The ultimate goal of candidate gene study is transporting, plasma membrane 2) gene [38]; to identify heritable genetic mutations in candi- WNT2 (wingless-type MMTV integration site fam- date genes that predispose an individual to autism, ily member 2), FOXP2 (forkhead box P2) and or to traits associated with autism. Candidate EN2 (Engrailed 2) genes [39-43]; SLC6A4 (5- genes that are involved in the cause of autism are HTT) (serotonin transporter)gene [44-45]; COMT genes whose product is known to play a role in (dopaminergic system - catechol-o-methyltrans- brain development or to be associated with brain ferase) gene [46 - 47]; CD157/BST1 gene [48]; structures, neurotransmitters, or neuromodulators CD38 Gene [49]; glutamate transporter genes implicated in autism on the basis of previous re- (GluR6, GRM7, GRIK2, GABRB3) [50 - 56]; search fi ndings. The other criteria make a gene eli- DAO (D-amino acid oxidase) and DAOA gible for the association studies include: the gene (D-amino acid oxidase activator) genes [57]; product is thought to be of relevance for behavior AVPR1A (arginine vasopressin receptor 1A gene) in humans; has been implicated through studies of [58]; TPH2 (tryptophan hydroxylase 2) [59]; animal models; has been identifi ed through a Homeobox (Hox) (DLX5, DLX6) genes [60]; Tsai LY • 143 •

MAOA (monoamine oxidase A) gene [61]; controls. While these numbers are not large, MTHFR (5,10 methylenetetrahydrofolate reduc- these are very rare mutations and as such repre- tase) [62 - 63]; OXT (oxytocin/neurophysin I), sent a signifi cant risk factor for autism in these OXTR (oxytocin receptor gene) [64-69]; ZNF533, populations [76]. DOCK4, IMMP2L genes [70]; ZNF407 gene [71]; ‧ Gau et al. (2012) report the detection of two Nephronophthisis 1 (NPHP1) gene [72]; FNDC3A novel private CNVs simultaneously in a male gene [73]; TRIM33 and NRAS-CSDE1 genes [74]. patient with autism. These two CNVs include a Table 1 shows the numbers of studies of microduplication at chromosome 4q12-13.1 above candidate genes that have been performed that was transmitted from his mother and a mi- in the three Asian populations. Overall, there are crodeletion at 5q32 that was transmitted from quite limited numbers of studies. his father. However, the parents had only mild degree of attention defi cit symptoms but did Copy Number Variation Study not demonstrate any obvious autistic symptoms or psychopathology. Copy number variations (CNVs) have be- The authors comment that their fi ndings indi- come the new paradigm in understanding com- cate that each of these two CNVs alone may not plex traits and diseases such as autism. A copy be pathogenic enough to cause clinical symp- number variation (CNV) is currently defi ned as a toms in their respective carriers, and hence they DNA segment longer than 1 kb, with a variable can be transmitted within each individual fam- copy number compared to a reference genome. A ily. However, concomitant presence of these CNV can be a deletion, insertion, duplication or two CNVs might result in the clinical pheno- a complex multi-site variant. It can be inherited types of the affected patient reported here. The or may arise de novo on a paternally or mater- authors speculate that two hits of CNV and the nally inherited chromosome. To be pathogenic, a presence of compound heterozygosity may be CNV must affect a gene in a molecular pathway important mechanisms underlying the patho- important in the development or maintenance of genesis of autism [77]. the human body. CNVs might change the tran- ‧ Rare (< 1% frequency) copy number variations scription rate of a gene product by increasing or (CNVs) account for a proportion of the genetic decreasing transcription, or in case of deletions, events involved, but the contribution of these they may unmask recessive mutations, or they events in non-European ASD populations has might change the coding sequence of a gene. not been well studied. Recently, Gazzellone et With the advance of micro-array-based compara- al. (2014) reported on rare CNVs detected in a tive genomic hybridization (array-CGH), it is cohort of individuals with ASD of Han Chinese now possible to also assess small cytogenetic ab- background [78]. normalities not detected by standard karyotyping DNA samples were obtained from 104 ASD [75]. It has been shown that de novo CNVs were probands and their parents who were recruited isolated in heterogenous genomic regions in from Harbin, China. Samples were genotyped ASD patients at frequencies which reached 10% on the Affymetrix CytoScan HD platform. Rare as compared to 3% in patients who had a fi rst- CNVs were identifi ed by comparing data with degree relative with ASD and only 1% in normal 873 technology-matched controls from Ontario • 144 • Autism Spectrum Disorder

Table 1. Autistic spetrun disorder candidate genes studies§ carried out in Asian populations

ASD Candidate Genes Han Chinese Japanese Korean NLGNS, NLGN4X, SHANK3 Yu et al. 2011 [23] Yanagi et al. 2012 [6] Xu et al. 2014 [25] Yasuda et al. 2011 [24] NRXN1 Liu et al. 2012 [26] CNTNAP2 Li et al. 2010 [27] SHANK Qin et al. 2009 [28] Waga et al. 2011 [29] Shao et al. 2014 [30] FABP Maekawa et al. 2010 [31] Shimamoto et al. 2014 [32] NDUFA5 Marui et al. 2011 [33] MET Zhou et al. 2011 [34] REELIN (RELN) Li et al. 2008 [35] Li et al. 2013 [36] Wang et al. 2014 [37] ATP2B2 Yang et al. 2013 [38] WNT2, FOXP2, EN2 Lin et al. 2012 [39] Chien et al. 2011 [40] Wang et al. 2008 [41] Yang et al. 2008 [42] Yang et al. 2010 [43] SLC6A4 (5-HTT) Cho et al. 2007 [44] Ro et al. 2013 [45] COMT Guo et al. 2013 [47] Yoo et al. 2013 [46] CD157/BST1 Yokoyama et al. 2015 [48] CD38 Munesue et al. 2010 [49] Glutamate transporter genes Shuang et al. 2005 [50] Kim et al. 2007 [52] Yang & Pan 2013 [51] Kim et al. 2006 [53] Chen et al. 2014 [56] Yoo et al. 2009 [5] DAO, DAOA Chung et al. 2007 [57] AVPR1A Yang et al. 2010 [58] TPH2 Yang et al. 2012 [59] Homeobox (DLX5, DLX6) Nakashima et al. 2010 [60] MAOA Gene Yoo et al. 2009 [61] MTHFR Guo et al. 2012 [62] Park et al. 2014 [63] OXT, OXTR Wu et al. 2005 [64] Kawamura et al. 2011 [66] Liu et al. 2010 [65] Ma et al. 2013 [68] Chen & Johnson 2012 [67] Saito et al. 2014 [69] ZNF533, DOCK4, IMMP2L Liang et al. 2014 [70] ZNF407 Ren et al. 2013 [71] NPHP1 Yasuda et al. 2014 [72] FNDC3A Ro et al. 2013 [73] TRIM33, NRAS-CSDE1 Xia et al. 2014 [74] §Numbers in parentheses are the references cited in this overview. Tsai LY • 145 •

and 1,235 additional population controls of ated with X chromosome-linked intellectual dis- Han Chinese ethnicity. ability; RELN, GluR6, GRIN2A, GRIN2B, and The authors found that 8.6% probands had at CNTNAP2 with schizophrenia, GABRB3 with least 1 de novo CNV (overlapping the GIGYF2, childhood absence epilepsy, 5-HTT with ADHD SPRY1, 16p13.3, 16p11.2, 17p13.3-17p13.2, and depression, and TPH2 with major depression DMD, and NAP1L6 genes/loci). Rare inherited [79]. CNVs affected other plausible neurodevelop- Despite the signifi cant heterogeneity in ASD, mental candidate genes including GRID2, these diverse studies identify several common ar- LINGO2, and SLC39A12. A 24-kb duplication eas of molecular convergence in ASD. was also identifi ed at YWHAE, a gene previ- Understanding how these pathways relate to indi- ously implicated in ASD and other develop- vidual differences now becomes an important re- mental disorders. This duplication is observed search priority [80]. at a similar frequency in cases and in population controls and is likely a benign Asian- AUTS2 gene specifi c copy number polymorphism. The in- ‧ The SNP rs6943555 in autism susceptibility vestigators conclude that their fi ndings help candidate 2 (AUTS2) has been reported to be defi ne genomic features relevant to ASD in the signifi cantly associated with alcohol consump- Han Chinese and emphasize the importance of tion in Europeans. Dang et al. (2014) examined using ancestry-matched controls in medical ge- the potential association between heroin depen- netic interpretations [78]. dence and 21 SNPs (rs2270162, rs2851510, rs513150, rs595681, rs210606, rs10237984, Genetic Common Pathway rs13228123, rs10235781, rs6969375, rs6943555, rs10251416, rs17141963, Molecular genetic studies in ASD have come rs12669427, rs723340, rs2293507, rs2293508, a long way from the early linkage studies, which rs6960426, rs9886351, rs2293501, rs10277450, aimed at describing a few loci and subsequently rs1918425) of AUTS2 in a Han Chinese popu- fi nding one or a few genes of major effect relevant lation using the MassARRAY system. The par- for all cases of ASD. Microarray studies are be- ticipants included 426 patients with heroin de- ginning to provide important insights into mole- pendence and 416 healthy controls. Single SNP cules and pathways that might be dysregulated association, haplotype association, and clinical across the ASDs and within individual subtypes of phenotype association were analyzed. pervasive developmental disorders. The authors found that SNP association ASDs are now becoming clear to be hetero- revealed that AA homozygotes of rs6943555 geneous disorders, caused by several rare—most were signifi cantly overrepresented in the pa- likely—monogenetic disorders (as fragile X syn- tients with heroin dependence compared with drome, mutations in TSC1/TSC2, LAMB1, the control subjects. The patients with heroin CNTNAP2, PTEN, DHCR7, SHANK3, NLGN3/4, dependence had a signifi cantly higher fre- or RPL10) [75]. Many ASD-related genes are also quency of the A allele (OR = 1.429). Strong associated with other neuropsychiatric disorders. linkage disequilibrium (LD) was observed in For example, IL1RAPL1 and OPHN1 are associ- fi ve blocks (D’ > 0.9). In block 2, signifi cantly • 146 • Autism Spectrum Disorder

more A-A haplotypes and signifi cantly fewer The authors conclude that CACNA1C may T-A haplotypes were found in the patients play a role in the genetic etiology of autism in with heroin dependence. The genotype and Chinese Han population [82]. clinical phenotype correlation study of the ‧ Park et al. (2014) performed interaction analy- rs6943555 carriers showed that the amount of sis between MAOA and FOXP2 in ASD, in- heroin selfi njection was lower in the patients cluding testing the verbal communication score with the AA genotype relative to AT + TT of the childhood autism rating scale. In interac- genotypes. tion analysis, the FOXP2-TCGC (rs12531289- The authors conclude that the results con- rs1350135-rs10230087-rs2061183) diplotype fi rmed that, in addition to heroin consumption, and MAOA-TCG (rs6323-rs1801291- the SNP rs6943555 of AUTS2 may also play an rs3027407) haplotype were signifi cantly asso- important role in the etiology of heroin depen- ciated with ASD in males. But when the inter- dence [81]. action term was omitted, neither MAOA nor FOXP2 was associated with ASD or verbal CACNA1C gene communication. ‧ To investigate the association between SNP in The authors conclude that the results indicate CACNA1C and autism, Li et al. (2015) fi rst per- that language and speech ability is affected by formed a family-based association study be- an interaction between FOXP2 and MAOA, but tween eighteen SNPs in CACNA1C and autism not by either gene separately [83]. in 239 Han Chinese trios [82]. All SNPs were genotyped by using Sequenom genotyping Genes not associate with ASD platform. Two SNPs (rs1006737 and There are several studies which conclude rs4765905) have a trend of association with au- that certain genes are not associated or there is tism. To further confi rm the association be- lacking of evidence of association with ASD. tween these two SNPs with autism, the authors ‧ Forkhead Box P2 (FOXP2) and protein-tyro- expanded the sample size to 553 trios by adding sine phosphatase, receptor-type, Zeta-1 314 trios. Association analyses for SNPs and (PTPRZ1) at the 7q region in Japanese patients haplotype were performed by using FBAT and [84]. Haploview software. Permutation tests were ‧ SLC6A4 in a Han Chinese population [85] and used for multiple testing corrections of the hap- in a Korean population [86] lotype analyses (n = 10,000). The signifi cance ‧ Norepinephrine transporter (SLC6A2) gene in level for all statistical tests was two-tailed (p < a Korean population [87] 0.05). The results demonstrate that G allele of ‧ Solute carrier family 25 member A12 rs1006737 and G allele of rs4765905 showed a (SLC25A12) gene in a Han Chinese population preferential transmission to affected offspring [87]. in 553 trios (p < 0.05). Haplotype analyses ‧ CDK5 (cyclin-dependent kinase 5), NDEL1, showed that two haplotypes constructed from and LIS1 in a Han Chinese population [88] rs1006737 and rs4765905 were signifi cantly ‧ GABA (c-aminobutyric acid) receptor genes associated with autism. These results were still (GABRB3, GABRA5, and GABRG3) in a signifi cant after permutation correction. Japanese population [89]. Tsai LY • 147 •

‧ Reelin gene (RELN) in a Han Chinese popula- thors conclude that their fi ndings suggest that tion [90]. extended recessive loci on 11q22.3 may play a ‧ NLGN3, NLGN4, SHANK2 and SHANK3 genes role in language impairment in autism [94]. in a Han Chinese population [91]. ‧ PTPRA gene in a Japanese population [92]. Clinical Implication ‧ dopa decarboxylase (DDC) and dopamine receptor-1 (DRD1) genes in a Han Chinese popu- Although our current understanding of the lation [93]. genetic implications of ASD is virtually in its in- fancy, the defi nite trend in the literature over the Mode of Inheritance past decade is for increased genetic screening/ testing and a decreasing threshold for obtaining Unraveling the mode of inheritance of ASD such tests. This is well-justifi ed as more is learned is complicated because of the very low incidence about the genetic causes of autism and as tests be- of either marriage or parenthood in individuals come more accurate and less expensive. As we with the autistic syndrome and of the tendency learn more about the genetic and molecular basis that the size of sibship decreased due to “stoppage of ASD, psychopharmacological interventions rule” (i.e., after having a child with autism, par- will be used to target specifi c genes and corre- ents tend to stop to have more children) which sponding behaviors. Thus, genetic screening/test- tends to cause underestimated familial aggrega- ing allows parents to have some answers regard- tion. Nevertheless, different modes of inheritance ing the source of their child’s ASD and to be able of ASD have been suggested. There is only one to obtain increased clarity about the course of Asian study which is marginally related to the their child’s disorder and target interventions most mode of inheritance of ASD. likely to be helpful for their child. ‧ To test if Runs of homozygosity (ROHs) are ‧ To determine whether a predictive model based linked to the risk of autism and related language on SNPs can predict symptom severity of ASD, impairment, Lin et al. (2013) analyzed 546,080 Jiao et al. (2012) divided 118 ASD children into SNPs in 315 Han Chinese affected with autism a mild/moderate autism group (n = 65) and a and 1,115 controls. ROH was defi ned as an ex- severe autism group (n = 53), based on the tended homozygous haplotype spanning at Childhood Autism Rating Scale (CARS). For least 500 kb. To search for the signature of se- each child, the authors obtained 29 SNPs of 9 lection sweeps, relative extended haplotype ho- ASD-related genes. To generate predictive mozygosity (REHH) for the trait-associated models, the authors employed three machine- ROH region was calculated. The authors identi- learning techniques: decision stumps (DSs), fi ed 676 ROH regions. An ROH region on alternating decision trees (ADTrees), and 11q22.3 was signifi cantly associated with FlexTrees. DS and FlexTree generated mod- speech delay. No evidence for recent positive estly better classifi ers, with accuracy = 67%, selection was detected on the core haplotypes sensitivity = 0.88 and specifi city = 0.42. The in this region. The same ROH region was also SNP rs878960 in GABRB3 was selected by all nominally signifi cantly associated with speech models, and was related associated with CARS delay in another independent sample. The au- assessment. The authors suggest that SNPs • 148 • Autism Spectrum Disorder

have the potential to offer accurate classifi ca- “hundreds” of ASD risk genes [101]. Heil and tion of ASD symptom severity [95]. Schaaf (2013) reported that more than 200 autism susceptibility genes had been identifi ed [102]. Summary Iossifov et al. (2012) estimated between 350 and 400 autism susceptibility genes had been identi- Autism spectrum disorder is a clinically fi ed [103]. Xu et al. (2012) performed a compre- complex childhood disorder. Etiology of ASD is hensive review and analysis of literature and data multifactorial, involving a strong genetic under- by using GWAS, genome-wide CNV studies, pinning. It was initially assumed that major ge- linkage analyses, low-scale genetic association nome-wide and candidate gene association studies studies, expression profi ling and other low-scale would lead most directly to common autism experimental studies [98]. They noted that as genes. But most discoveries have come from stud- many as 2193 genes, 2806 SNPs/VNTRs, 4544 ies of known genetic disorders associated with the copy number variations (CNVs) and 158 linkage behavioral phenotype. regions had been associated with ASD. They then Multiple lines of evidence support the notion used a scoring and ranking approach to select a that most cases of autism likely have an underly- core data set of 434 high-confi dence genes as ing genetic cause or predisposition. Furthermore, ASD risk genes [98]. ASD is likely to be caused by many different ge- In this overview, I have found impressive netic mechanisms and genes rather than a single, amount of ASD genetic studies being carried out or few, major genes or environmental effects. by Asian countries (China, Japan, Korea and Although certain progress in autism genetic Taiwan). Although, these Asian countries have study has been made in the last decades and sev- made some strides, comparing to the above fi nd- eral autism susceptibility genes and loci have been ings from Western countries, they still have a long identifi ed, for the majority of individuals with way to go before catching up with Western coun- ASD (70% - 80%), the causes of the disorder re- tries’ progress in the fi eld of ASD genetics. In this main unknown [96, 97]. It is unclear how many overview, I have found that there are three meta- genes have been associated with ASD and how analysis genetic studies that had included Asian strong the evidence is [98]. Bespalova and samples. In the fi rst study, only one out of eight Buxbaum (2003) suggested that family studies included studies is an Asian sample [104] ; in the and several genome-wide linkage analyses sup- second study, only two out of seven studies are ported the hypothesis of complex inheritance with Asian samples [37]; in the third study, only two involvement of as many as 10-100 genes of mod- out of nine included studies are Asian samples erate effect [99]. Geschwind (2011) reported that [105]. It is obvious that more high quality ASD several dozen ASD susceptibility genes had been genetic studies are needed to contribute to the identifi ed in the past decade [80]. Kumar et al. worldwide understanding of ASD genetics. (2011) used a reference set of 84 rare and syn- This overview has found a few Asian ASD dromic candidate ASD genes (AutRef84) to screen genetic studies that have addressed to the ethnic the human genome and were able to derive a set of differences in certain candidate genes. These stud- 460 potential ASD candidate genes [100]. Devlin ies provide support to the notion of paying atten- and Scherer (2012) suggested the existence of tion to ethnic differences when attempting to draw Tsai LY • 149 •

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