Research Article Association of a miRNA-137 Polymorphism...

Research ArticleAssociation of a miRNA-137 Polymorphism with Schizophreniain a Southern Chinese Han Population

Guoda Ma1 Jingwen Yin2 Jiawu Fu1 Xudong Luo2 Haihong Zhou1 Hua Tao1

Lili Cui1 You Li1 Zhixiong Lin2 Bin Zhao1 Zheng Li3 Juda Lin2 and Keshen Li1

1 Institute of Neurology Guangdong Medical College Zhanjiang 524001 China2Department of Psychiatry Affiliated Hospital of Guangdong Medical College Zhanjiang 524001 China3Unit on Synapse Development and Plasticity National Institute of Mental Health National Institutes of HealthBethesda MD 20892 USA

Correspondence should be addressed to Juda Lin linjuda126com and Keshen Li likeshen1971126com

Received 13 June 2014 Accepted 6 August 2014 Published 27 August 2014

Academic Editor Luke Hesson

Copyright copy 2014 Guoda Ma et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Both genome wide association study (GWAS) and biochemical studies of Caucasian populations indicate a robust associationbetween the miR-137 genetic variant rs1625579 and schizophrenia but inconsistent results have been reported To assay theassociation between this variant and schizophrenia we genotyped 611 schizophrenic patients from Southern Chinese Hanpopulation for the risk single nucleotide polymorphism (SNP) rs1625579 using the SNaPshot technique and compared the clinicalprofiles of different genotypes Additionally a meta-analysis was performed using the combined sample groups from five case-control publications and the present study Both the genotype and allele distributions of the rs1625579 SNP were significantlydifferent between patients and controls (119875 = 0036 and 0026 SNP) TT genotype carriers showed slightly lower Brief Assessmentof Cognition in Schizophrenia- (BACS-) derived working memory performance than G carriers (1558 plusmn 956 versus 1971 plusmn818 119875 = 0045) In the meta-analysis we observed a significant association between rs1625579 and schizophrenia underdifferent genetic models (all 119875 lt 005) The results of our study and meta-analysis provide convincing evidence that rs1625579 issignificantly associatedwith schizophrenia Furthermore themiR-137 polymorphism influences theworkingmemory performanceof schizophrenic patients in a Chinese Han population

1 Introduction

miRNAs are small noncoding RNAs that regulate geneexpression posttranscriptionally [1] Over half of themiRNAsidentified thus far are highly or exclusively expressed inthe brain where they act as integral regulators of neuronalgenes involved in the function plasticity and development ofthe brain [2 3] miRNAs and their regulatory networks arethought to contribute to the complex processes underlyingthe etiology and pathophysiology of psychiatric disordersincluding schizophrenia [4ndash6]

Hsa-miR-137 as a brain-enrichedmicro-RNA has impor-tant roles during neurogenesis including the proliferationand differentiation of neural stem cells the regulation ofdendritic morphogenesis and synaptic plasticity [2 7 8]

Furthermore miR-137 is a candidate gene for schizophreniasusceptibility and was identified by a recent mega-GWASanalysis in the sample of European ancestry conductedby the Psychiatric GWAS Consortium (PGC) [9] where apolymorphism (rs1625579) located in the primary transcriptof hsa-miR-137 had the strongest genetic signal associatedwith schizophrenia Moreover four other schizophreniaassociated genes (TCF4 CACNA1C CSMD1 and C10orf26)identified in that study contain predicted miR-137 bindingsites [10] suggesting that the interplay between miR-137and its target genes could be involved in the etiology ofschizophrenia [11ndash13]

Since the publication of the 2011 GWAS study [9] manysubsequent independent studies have suggested a significantheterogeneity for the rs1625579 polymorphism of miR-137 in

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 751267 8 pageshttpdxdoiorg1011552014751267

2 BioMed Research International

Table 1 The demographic characteristics of schizophrenic patientsand controls

VariablesSchizophrenic

patients Controls Statisticaltests

(119899 = 611) (119899 = 628)Mean age plusmn SD(year) 3556 plusmn 1395 3654 plusmn 1214 119905 = 1331

119875 = 0183Gender 119899 ()

Male 397 (6498) 417 (6640) 1205942 = 0279119875 = 0597Female 214 (3502) 211 (3360)

SD standard deviation

schizophrenia across ethnicities [14ndash18] Recently Guan et al[19] also found that the rs1625579 locus was associated withschizophrenia risk in a Northern Chinese cohort Howeverthey did not report the effects of miR-137 on certain traitsof schizophrenia such as age at onset clinical symptomsand cognitive functions In the present study we conducteda hospital-based case-control study to address this questionin a Southern Chinese Han population and confirmed ourfindings in a meta-analysis with previously published popu-lations Moreover we also evaluated the association betweenmiR-137 polymorphism and the clinical characteristics ofschizophrenia

2 Subjects and Methods

21 Subjects We recruited 611 schizophrenic patients and 628healthy controls from the affiliated hospital of GuangdongMedical College All patients underwent a standardized bat-tery of examinations including family history extensive drugand alcohol assessment physical and neurological exami-nation and laboratory tests to exclude substance-inducedpsychotic disorders or psychosis caused by general medicalcondition The diagnosis was assigned independently by twoexperienced senior psychiatrists based on the Diagnosticand Statistical Manual of Mental Disorders IV (DSM-IV)Psychotic symptoms were evaluated in accordance withstructured interviews for the Positive and Negative SymptomScale (PANSS) The healthy controls were recruited from theMedical Center of the affiliated hospital of Guangdong Med-ical College Based on unstructured interviews participantswho had a personal or family history of major psychiatricdisorders serious somatic illnesses and substance abusewere excluded The patients and controls were comparablein age and sex distribution (Table 1) The study protocol wasapproved by the ethics committee of Guangdong MedicalCollege andwritten informed consent was obtained from theparticipants andor direct relatives

22 DNA Extraction and Genotyping DNA from bloodsamples was extracted using the Blood DNA Kit (TiangenChina) SNP rs1625579 was genotyped using the SNaPshottechnique with polymerase chain reaction (PCR) primers51015840-TTTAGTCAACATTTGCATTTGGAAGC-31015840 and 51015840-CAACAGATTCCAAAGGTCTCTAGTGTGC-31015840 PCR wasperformed in a 20120583L reaction composed of 1 times GC Buffer

30mMMg2+ 03mM dNTPs 1 U of HotStarTaq polymerase(Qiagen Germany) 1120583L of template DNA (each at a finalconcentration of 5ndash10 ng120583L) and 2 120583L of PCR primersAmplification was performed with the following program2min at 95∘C followed by 11 cycles of 94∘C for 20 s 65∘Cplusmn 05∘Ccycle for 40 s and 72∘C for 15min and then 24cycles consisting of 94∘C for 20 s 59∘C for 30 s and 72∘C for15min with a final extension step at 72∘C for 2min Theextension primer was 51015840-TTTTTTTTTTTTTTTTTTTTT-AAACAAGGGAAATGTTAATCACAATTA-31015840The single-nucleotide primer extension reaction was conducted usingthe ABI PRISM SNaPshot Multiplex Kit Protocol (AppliedBiosystems USA) Then 05120583L of the purified single baseextension products was mixed with 9120583L of Hi-Di formamideand 05 120583L of GeneScan-LIZ 120 internal size standard Aftera denaturing step for 2min at 95∘C followed by cooling to 5∘Cthe mixture was further analyzed by capillary electrophoresisusing anABI Prism 3130xl Genetic Analyzer (Applied Biosys-tems USA) The data were analyzed using GeneMapper 41(Applied Biosystems USA)

23 Neurocognitive Function Assessment The Brief Assess-ment of Cognition in Schizophrenia (BACS) assesses thedifferent aspects of cognition found to be important forcognitive impairment in patients with schizophrenia (1)verbal memory measured by List Learning (2) workingmemory measured by the Digit Sequencing Task (3) motorspeed measured by the Token Motor Task (4) verbal fluencyassessed using the Category Instances and Controlled OralWord Association Test (5) reasoning and problem solvingassessed using the Tower of London and (6) attentionand processing speed assessed using Symbol Coding Thebattery of tests requires approximately 30ndash35 minutes tocomplete in patients with schizophrenia and is scored by twopsychologists Further details on the BACS assessment werereported elsewhere by Keefe et al [20 21]

Meta-Analysis The references included in the analysiswere searched using Pubmed (httpwwwncbinlmnihgovpubmed) HighWire Press (httphighwirestanfordedu)China National Knowledge Infrastructure (CNKI httpwwwcnkinet) and Google Scholar (httpscholargooglecom) without any language limitations focusing on thekeywords ldquoschizophreniardquo and ldquomiR-137rdquo or ldquomicroRNA-137rdquoThe literature search was updated on May 10th 2014 Thecriteria for inclusion were as follows association studieswritten in English diagnosis of schizophrenia accordingto standardized criteria such as DSM or ICD-10 case-control studies investigating rs1625579 genotype and allelefrequencies available genotyping method and sufficient datato calculate the odds ratio (OR)with 95confidence intervals(CI) and 119875 values The following were exclusion criteriareviews or abstracts studies which were not relevant to miR-137 gene rs1625579 polymorphism or schizophrenia studieswhich did not report genotype frequencies The flow of thearticle selection process was shown in Figure 1 In total fiveindependent case-control studies were selected [14 16ndash19]Then the following information was extracted from each

BioMed Research International 3

Full articles obtained for further review (n = 14)

Excluded based on titles and abstracts (n = 11)

Not relevant studies (n = 10)

Excluded after full-text review (n = 7)Not report schizophrenia (n = 3)

Irrelevant polymorphism (n = 1)

Articles included in meta-analysis (n = 5)

Articles included in systematic review and data extracted (n = 7)

Reviews meta-analysis and editorial (n = 1)

Not reporting genotypes or alleles (n = 3)

Excluded from meta-analysis (n = 2)

Not case-control study (n = 1)No detailed genotype frequency (n = 1)Duplicates (n = 0)

HighWire Press (n = 10)

Potential relevant articles (n = 25)

PubMed (n = 15)

CNKI (n = 0)

Figure 1 Flow diagram of the article selection process

study the name of first author the year of publicationthe ethnicity of the study population the numbers andfrequencies of rs1625579 polymorphism genotypes in casesand controls the OR with 95 CI or if not providedcalculated the OR and 95 CI The quality evaluation wasperformed with the Newcastle-Ottawa Quality AssessmentScale for case-control studies

We evaluated the genetic heterogeneity among the studiesincluded using Cochranrsquos119876 test which approximately followsa 1205942 distribution with 119896 minus 1 degrees of freedom (119896 stands forthe number of studies for analysis) Another statistic 1198682 =((119876 minus (119896 minus 1))119876) times 100 was also used 1198682 ranges from 0 to100 [22] Low moderate large and extreme heterogeneitycorresponded to 0ndash25 25ndash50 50ndash75 and 75ndash100respectively [22] We defined the significant heterogeneitywith 119875 lt 001 and 1198682 gt 50

All statistical tests for heterogeneity and meta-analysis were performed using RevMan (v51) software(httpimscochraneorgrevmandownload) If there wasno significant heterogeneity among the total of six studiesincluding the present study (total of 3133 patients and 2791controls) OR with corresponding 95 CI was calculatedby the fixed effect model (Mantel-Haenszel) otherwise theOR was calculated by random-effect model (DerSimonian-Laird) 119885 test was used to determine the significance ofOR

Four genetic models were used in our meta-analysiswhich can be described as follows the dominant model (TT+ GT versus GG) the recessive model (TT versus GT +GG) the additive model (TT versus GG) and the allelemodel (T allele versus G allele) In order to validate thestability of our results sensitivity analysis for the overall

effect was performed by omitting one case-control study at atime Additionally the publication bias was investigated withEggerrsquos test and Beggrsquos test using Stata 120 software

3 Statistical Analysis

Hardy-Weinberg equilibrium was tested using Pearsonrsquos chi-squared test Given the low frequency of the GG geno-type in both schizophrenic patients (05) and controls(10) these cases were combined with those having theGT genotype to form the ldquoG-allele carrierrdquo group for allstatistical tests Statistical analyses comparing allelic andgenotypic distributions were performed using Pearsonrsquos chi-squared test or Studentrsquos 119905-test Generalized ORs with 95CIs of the alleles were calculated Descriptive variables werepresented as the mean plusmn standard deviation (SD) 119875 lt005 was considered significant for all statistical tests Thestatistical analysis was performed using SPSS190 softwareand the power calculation was performed using QUANTO12 software (httpbiostatsuscedusoftware)

4 Results

The distribution of the miR-137 rs1625579 polymorphism inour cohort is described inTable 2 Both the schizophrenia andcontrol populations were inHardy-Weinberg equilibrium (all119875 gt 005) The frequency of the TT TG and GG genotypeswas 9002 (119899 = 550) 966 (119899 = 59) and 033 (119899 = 2)respectively in the schizophrenic patients and 8615 (119899 =541) 1306 (119899 = 82) and 080 (119899 = 5) respectively inthe controls Because of the high prevalence of the presumedrisk allele (T) we conducted the analysis according to the


Table 2 Genotype and allele frequencies of miR-137 gene rs1625579 polymorphism in schizophrenic patients and controls

119873Genotype 119899 ()

1205942119875

Allele 119899 ()1205942119875

HWE OR 95 CITT GT + GG T G 120594

2119875

TotalPatients 611 550 (9002) 61 (998) 4409 0036lowast 1159 (9484) 63 (516) 4971 0026lowast 0097 0756 1450a 1024ndash2054Control 628 541 (8615) 87 (1385) 1164 (9268) 92 (732) 0919 0338 1454b 1045ndash2024

MalePatients 397 353 (8892) 44 (1108) 2275 0131 748 (9421) 46 (579) 2562 0109 0377 0539 1375a 0908ndash2081Control 417 356 (8537) 61 (1463) 769 (9221) 65 (779) 0999 0317 1374b 0930ndash2032

FemalePatients 214 197 (9206) 17 (794) 2240 0135 411 (9603) 17 (397) 2548 0110 0366 0545 1629a 0856ndash3099Control 211 185 (8768) 26 (1232) 395 (9360) 27 (640) 0025 0876 1653b 0887ndash3079

aCalculations were performed TT versus GT + GG bcalculations were performed T versus G lowast119875 lt 005HWE Hardy-Weinberg equilibrium OR odds ratio 95 CI 95 confidence interval nucleotides G = guanine T = thymine

Table 3 Analysis of clinical characteristics between patients with TT and GT + GG genotypes

Variables 119873 (TTGT + GG) Genotype Statistic tests 119875TT GT + GG

Age (Mean plusmn SD year) 55061 3635 plusmn 1404 3741 plusmn 1306 119905 = 1095 0274Disease duration (Mean plusmn SD year) 55061 1043 plusmn 1011 1049 plusmn 938 119905 = 0045 0964Age at onset (Mean plusmn SD year) 55061 2458 plusmn 1024 2682 plusmn 1093 119905 = 1611 0108Male 34844 2385 plusmn 901 2505 plusmn 968 119905 = 0824 0411Female 19517 2676 plusmn 1114 3142 plusmn 1286 119905 = 1630 0105Family history + 119899 () 798 79 (9080) 8 (920)

1205942 = 0070 0791

Family history minus 119899 () 47153 471 (8989) 53 (1011)PANSS (Mean plusmn SD)

Total score 53360 8016 plusmn 1827 7952 plusmn 1930 0258 0796P subscore 53360 2245 plusmn 726 2188 plusmn 753 0575 0565N subscore 53360 1833 plusmn 812 1923 plusmn 695 0831 0406G subscore 53360 3683 plusmn 892 3638 plusmn 894 0362 0717

BACS (Mean plusmn SD)Digit sequencing task 18524 1558 plusmn 956 1971 plusmn 818 2016 0045lowast

Category instances 18524 3092 plusmn 1267 3179 plusmn 1219 0317 0752Controlled oral word association test 18524 1004 plusmn 607 1004 plusmn 521 0001 0999List learning 18524 2229 plusmn 1261 2133 plusmn 1393 0346 0730Token motor task 18524 4614 plusmn 1183 4629 plusmn 1264 0061 0952Tower of London 18524 762 plusmn 685 750 plusmn 112 0083 0934Symbol coding 18524 2112 plusmn 1268 1871 plusmn 1231 0881 0379

lowast119875 lt 005

SD standard deviation PANSS Positive and Negative Syndrome Scale P Positive scale N Negative scale G General Psychopathology scale BACS BriefAssessment of Cognition in Schizophrenia

presence of two copies of the risk allele (TT) or only one orno copies (GT or GG resp) A significant association wasobserved between the case and control groups for genotype(1205942 = 4409 119875 = 0036) and allele (1205942 = 4971 119875 = 0026)

Power was calculated using a G allele frequency of 0073Our entire cohort had a power of 0813 for detecting agenotype relative risk with an OR of 15 at the 005 levelTherefore our finding could be statistically strong with anappropriate sample size

When the samples were stratified according to sex wedid not find any significant difference in either the genotype

(1205942 = 2275 119875 = 0131 for male 1205942 = 2240 119875 = 0135for female) or allele (1205942 = 2562 119875 = 0109 for male 1205942 =2548 119875 = 0110 for female) distributions Additionally wefocused on the description of relevant clinical characteristicsNo significant differences were observed with regard to agedisease duration age at onset family history and PANSSclinical symptom scores (Table 3)

Neurocognitive functions were determined using BACSThe sample for neurocognitive testing consisted of 209clinically stable patients As shown in Table 3 we observedthat the T allele for SNP rs1625579 was associated with lower


digit sequencing scores (119905 = 2016 119875 = 0045) There was nosignificant difference in the scores of the other BACS items

In the meta-analysis derived from five published case-control studies and the present association study no sig-nificant heterogeneity was observed in the total analysiswith different models (1198682 = 00 for all genetic models)Associations however were observed betweenmiR-137 poly-morphism and schizophrenia using a dominant model (119875 =003 OR = 151 95 CI 104ndash220) recessive model (119875 =0001 OR = 123 95 CI 108ndash139) additive model (119875 =002 OR = 158 95 CI 108ndash229) and allele model (119875 =00004 OR= 122 95CI 109ndash136) (Figure 2)Therewas nosignificant publication bias for the dominant model (Beggrsquostest 119875 = 045 and Eggerrsquos test 119875 = 053) recessive model(Beggrsquos test 119875 = 100 and Eggerrsquos test 119875 = 097) additivemodel (Beggrsquos test 119875 = 045 and Eggerrsquos test 119875 = 056)or allele model (Beggrsquos test 119875 = 100 and Eggerrsquos test 119875 =083) The sensitivity analysis indicated that no single studyqualitatively affected the summary risks (data not shown)

5 Discussion

The miR-137 gene was highly associated with schizophreniain a recent GWAS analysis with an initial sample sizeof 21856 and a replication sample size of 29839 [9] Intwo accompanying papers five schizophrenia susceptibil-ity genes including CSMD1 C10orf26 CACNA1C TCF4and ZNF804A were validated as miR-137 targets [10 23]providing additional evidence for the involvement of miR-137 in schizophrenia Along these lines Wright et al [24]recently used bioinformatic tools to examine putative targetsof miR-137 and their potential contributions to neuronalfunctionsThe top scoring pathways predicted byWright et alare related to long-term potentiation (LTP) ephrin receptorsignaling and axonal guidance all of which are associatedwith learning memory and synaptic formation and areimpaired in schizophrenia [25 26] Importantly a recentpostmortem study showed that miR-137 was downregulatedin the dorsolateral prefrontal cortex of schizophrenic patients[27] Together these findings suggest that dysregulation ofmiR-137 may contribute to the pathology of schizophrenia

In an attempt to replicate the GWAS findings in Asiansubjects we examined the miR-137 rs1625579 polymorphismin a Chinese Han cohort comprising 611 schizophrenicpatients and 628 healthy controls Significant differences inthe genotype or allele distribution of the rs1625579 SNP wereidentified between schizophrenic patients and controls (1205942 =4409 119875 = 0036 and 1205942 = 4971 119875 = 0026 resp) Theseresults were replicated in a meta-analysis (119875 = 003 OR =151 95 CI 104ndash220 for the dominant model 119875 = 0001OR= 123 95CI 108ndash139 for the recessivemodel119875 = 002OR = 158 95 CI 108ndash229 for the additive model and119875 = 00004 OR = 122 95CI 109ndash136 for the allelemodel)The data demonstrate that the miR-137 polymorphism mayaffect susceptibility to schizophrenia under a recessive modelfor the T alleleThis finding is in agreement with a GWAS [9]and a previous study in a northern Chinese cohort of Xirsquoanby Guan et al [19] In the present study the frequency of the

GG genotype was extremely low in schizophrenic patientsand healthy controls (033 in the cases and 080 in thecontrols) Additionally a lower frequency of the rs1625579G-allele was detected in our cohort from Southern China(516 in the cases and 732 in the controls) than previouslyobserved in American and Canadian (1765 in the casesand 2066 in the controls) [17] Australian (1945 in thecases and 2088 in the controls) [16] and Scottish (2685in the cases and 2037 in the controls) [14] populationsThese values reveal an ethnic heterogeneity in the distributionof the miR-137 polymorphism In the same ethnicity the Gallele frequency of rs1625579 in our cohort from Zhanjiangin Southern China was also markedly lower than that inthe Chinese cohort of Xirsquoan from a previous study [19](119 in the cases and 142 in the controls) but similarto the level in the Chinese population in Beijing from theInternationalHapMap Project (theminor allele frequencies =0085) (httphapmapncbinlmnihgov) Therefore geneticvariation of miR-137 also exists among geographic groupswithin the Chinese population However our results andmeta-analysis provide further support for the associationbetween miR-137 polymorphism and schizophrenia evenwith the lower frequency of the G allele

Our study demonstrated a weak but significant asso-ciation between the TT genotype and lower scores indigit sequencing for working memory in the Chinese Hanpopulation which is similar to the results of Cummingset al [15] who showed that the polymorphism rs1625579was also associated with cognitive deficits in schizophreniaincluding working memory (assessed using the CANTABSpatial Working Memory task) (119875 lt 00001) In additionoverlapping microdeletion of the miR-137 locus in the chro-mosomal region 1p213 has been identified in patients withintellectual disabilities [28]Therefore we speculate thatmiR-137 is a key regulator in learning and memory processesConsidering that cognitive impairment is involved in thedevelopment of dysfunctional (neural synaptic) connectivitybetween brain regions [29 30] the lower performance ofworking memory associated with the TT genotype in ourpatients may be ascribed to inefficiency in neural func-tioning which is regulated by miR-137 polymorphism Thisviewpoint is supported by van Erp et al [18] who foundthat lower working memory performance was related tohigher left dorsolateral prefrontal cortex (DLPFC) activationin schizophrenic patients Although there was no effect ofgenotype on workingmemory performance in schizophrenicpatients individuals with the rs1625579 TT genotype hadsignificantly higher left DLPFC activation than those withthe GGGT genotypes during a working memory test Thisworking memory-associated DLPFC hyperactivation wasinterpreted as being consistent with neural inefficiency incarriers of the rs1625579 schizophrenia risk allele This find-ing also showed that rs1625579 affected other neuroimagingphenotypes of schizophreniaTheT allele was associatedwithdecreased hippocampal volume and reduced white matterintegrity throughout the entire brain in the study by Lett et al[17] In our research BACS assessment was only conductedon 209 samples approximately 13 of the original cohortConsidering the limited sample size in this analysis we


Study or subgroup

2012

2013

2013

2013

2014

2014

Schizophrenia

Events Total Events Total

ControlWeight

Odds ratioYear

Odds ratio

109 [010 1235]166 [097 285]111 [055 224]153 [054 432]244 [047 1264]394 [018 8406]

284773241144512

811570

328

121

628

63

791532

314

116

623

61

441429

491

510

611

48

431408

472

496

609

48

111 TT + GT versus GG

112 TT versus GT + GG

114 T versus G

Whalley et al [Scottish]Guan et al [Chinese]Green et al [Australian]Lett et al [CanadianAmerican]Our study [Chinese]van Erp et al [American]

3133 2791Total events 3076 2725

Heterogeneity 1205942 = 165 df = 5 (P = 090) I2 = 0

Test for overall effect Z = 218 (P = 003)

1000 151 [104 220]Subtotal (95 CI)

2012

2013

2013

2013

2014

2014

123 [104 145]111 [083 149]123 [081 185]

325501928917119

811570

328

121

63

628

501162

205

76

46

541

441429

491

510

48

611

261111

319

344

39

550

Whalley et al [Scottish]Guan et al [Chinese]Green et al [Australian]Lett et al [CanadianAmerican]van Erp et al [American]

3133 2791Total events 2389 2080



1000 123 [108 139]Subtotal (95 CI)

090 [042 190]

160 [064 399]145 [102 205]Our study [Chinese]

002)

2012

2013

2013

2013

2014

2014

104 [009 1201]115 [056 234]173 [101 297]162 [057 462]254 [049 1316]425 [020 9112]

293214811114512

52219

1200

81

546

48

50205

1162

76

541

46

27338

1132

358

552

39

26319

1111

344

550

39

Whalley et al [Scottish]

Guan et al [Chinese]Green et al [Australian]

Lett et al [CanadianAmerican]Our study [Chinese]van Erp et al [American]

2446 2146Total events 2389 2080


Test for overall effect Z = 238 (P =

1000 158 [108 229]Subtotal (95 CI)

00004)

2012

2013

2013

2013

2014

2014

122 [086 173]123 [106 143]109 [085 140]

35

536213

15

162242

3140

656

1256

126

129192

2694

519

1164

107

881020

2858

982

1222

96

69840

2519

791

1159

87



Lett et al [CanadianAmerican]

Our study [Chinese]van Erp et al [American]

6266 5582Total events 5465 4805



1000 122 [109 136]Subtotal (95 CI)

113 TT versus GG

093 [049 175]

145 [104 202]172 [074 398]

96

104

002 01 1 10 50

M-H fixed 95 CI M-H fixed 95 CI

Figure 2 Forest plot of the meta-analysis for an association between the rs1625579 polymorphism and schizophrenia using dominantrecessive additive and allele models 111 dominant model (TT + GT versus GG) 112 recessive model (TT versus GT + GG) 113 additivemodel (TT versus GG) 114 allele model (T versus G) M-H Mantel-Haenszel Fixed fixed effect model CI confidence interval

cannot exclude the possibility that the statistical significanceis due to the occurrence of the type I error Given thesepossibilities a replication study with lager sample size wouldbe helpful in addressing this limitation and giving a moredefinitive view of the results reported in this present study

We failed to find an association between rs1625579 andother clinical characteristics of schizophrenia including ageonset and PANSS scores However recent investigations havedemonstrated an association of this variant with age ofpsychosis onset and schizophrenia symptoms One recent


publication found that the T allele of miR-137 rs1625579is associated with an earlier age of onset in schizophrenia[17] In another recent study with a mixed sample of bipo-lar disorder I schizoaffective disorder and schizophreniapatients the risk variant was also associated with lowerpositive symptom scores [15] Green et al [16] found thatthe G-allele was associated with a specific schizophreniaphenotype characterized by severe cognitive impairment andnegative symptoms However these studies did not show aconsistent pattern of miR-137 polymorphism with regard toany clinical or neurobiological variables of schizophreniaDifferences in the distribution of allele frequency diagnosticcriteria symptoms and cognitive measures may limit thepower of these studies to detect association particularly incase-control studies

Although the biology underlying the observed asso-ciation of the miR-137 rs1625579 polymorphism remainsunclear it has been noted that the T allele of rs1625579 maybe associated with a decrease in miR-137 expression in thecerebral cortex [27] miR-137 is likely a central factor coor-dinating the timing and expression of multiple schizophreniarisk genes especially those related to neuronal differentiationand proliferation [2 8 10 24 31 32] Thus we suspectthat dysregulation of miR-137 expression and the subsequentabnormal expression ofmiR-137 target genes contribute to theneurodevelopment disease progression and neuromorpho-logical pathologies present in schizophrenia [33]

In conclusion the results of our case-control study andmeta-analysis provide convincing evidence that the miR-137 rs1625579 polymorphism is significantly associated withschizophrenia risk In addition the rs1625579 polymorphismmodifies working memory performance in Chinese Hanpatients with schizophrenia Further investigations on thefunctional consequences of miR-137 polymorphismmay helpto elucidate the molecular mechanisms by which this geneticvariant affects the schizophrenic phenotype

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

GuodaMa and Jingwen Yin contributed equally to this work

Acknowledgments

This work was supported by funding from the US-ChinaBiomedical Collaborative Research Program (Grant no81261120404) the National Nature Science Foundation ofChina (Grant nos 31171219 81271213 81471294 and 81271214)and the Science and Technology Innovation Fund of Guang-dong Medical College (no STIF 201101)

References

[1] D P Bartel ldquoMicroRNAs genomics Biogenesis Mechanismand Functionrdquo Cell vol 116 no 2 pp 281ndash297 2004

[2] K E Szulwach X Li R D Smrt et al ldquoCross talk betweenmicroRNA and epigenetic regulation in adult neurogenesisrdquoJournal of Cell Biology vol 189 no 1 pp 127ndash141 2010

[3] D O Perkins C D Jeffries L F Jarskog et al ldquomicroRNAexpression in the prefrontal cortex of individuals withschizophrenia and schizoaffective disorderrdquo Genome Biologyvol 8 no 2 article R27 2007

[4] B H Miller and C Wahlestedt ldquoMicroRNA dysregulation inpsychiatric diseaserdquo Brain Research vol 1338 pp 89ndash99 2010

[5] H I Im and P J Kenny ldquoMicroRNAs in neuronal function anddysfunctionrdquoTrends inNeurosciences vol 35 no 5 pp 325ndash3342012

[6] B Xu M Karayiorgou and J A Gogos ldquoMicroRNAs inpsychiatric and neurodevelopmental disordersrdquoBrain Researchvol 1338 pp 78ndash88 2010

[7] J Silber D A Lim C Petritsch et al ldquomiR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cellsand induce differentiation of brain tumor stem cellsrdquo BMCMedicine vol 6 article 14 2008

[8] R D Smrt K E Szulwach R L Pfeiffer et al ldquoMicroRNAmiR-137 regulates neuronal maturation by targeting ubiquitin ligasemind bomb-1rdquo Stem Cells vol 28 no 6 pp 1060ndash1070 2010

[9] Schizophrenia Psychiatric Genome-Wide Association StudyConsortium ldquoGenome-wide association study identifies fivenew schizophrenia locirdquo Nature Genetics vol 43 no 10 pp969ndash976 2011

[10] E Kwon W Wang and L-H Tsai ldquoValidation of schiz-ophrenia-associated genes CSMD1 C10orf26 CACNA1C andTCF4 as miR-137 targetsrdquo Molecular Psychiatry vol 18 no 1pp 11ndash12 2013

[11] L Lennertz B B Quednow J Benninghoff M Wagner WMaier and R Mossner ldquoImpact of TCF4 on the genetics ofschizophreniardquo European Archives of Psychiatry and ClinicalNeuroscience vol 261 no 2 pp S161ndashS165 2011

[12] S Bhat D T Dao C E Terrillion et al ldquoCACNA1C (Cav12) in the pathophysiology of psychiatric diseaserdquo Progress inNeurobiology vol 99 no 1 pp 1ndash14 2012

[13] J Yin J Lin X Luo Y Chen Z Li and G Ma ldquomiR-137 anew player in schizophreniardquo International Journal ofMolecularSciences vol 15 no 2 pp 3262ndash3271 2014

[14] H C Whalley M Papmeyer L Romaniuk et al ldquoImpact of amicroRNA MIR137 susceptibility variant on brain function inpeople at high genetic risk of schizophrenia or bipolar disorderrdquoNeuropsychopharmacology vol 37 no 12 pp 2720ndash2729 2012

[15] E Cummings G Donohoe A Hargreaves et al ldquoMoodcongruent psychotic symptoms and specific cognitive deficitsin carriers of the novel schizophrenia risk variant at MIR-137rdquoNeuroscience Letters vol 532 no 1 pp 33ndash38 2013

[16] M J Green M J Cairns J Wu et al ldquoGenome-wide supportedvariant MIR137 and severe negative symptoms predict mem-bership of an impaired cognitive subtype of schizophreniardquoMolecular Psychiatry vol 18 no 7 pp 774ndash780 2013

[17] T A Lett M M Chakavarty D Felsky et al ldquoThe genome-wide supported microRNA-137 variant predicts phenotypicheterogeneity within schizophreniardquoMolecular Psychiatry vol18 no 4 pp 443ndash450 2013


[18] T G M van Erp I Guella M P Vawter et al ldquoSchizophreniamiR-137 locus risk genotype is associated with dorsolateralprefrontal cortex hyperactivationrdquo Biological Psychiatry vol 75pp 398ndash405 2014

[19] F Guan B Zhang T Yan et al ldquoMIR137 gene and target geneCACNA1C of miR-137 contribute to schizophrenia susceptibil-ity in Han Chineserdquo Schizophrenia Research vol 152 no 1 pp97ndash104 2014

[20] R S E Keefe M Poe T M Walker and P D HarveyldquoThe relationship of the Brief Assessment of Cognition inSchizophrenia (BACS) to functional capacity and real-worldfunctional outcomerdquo Journal of Clinical and ExperimentalNeuropsychology vol 28 no 2 pp 260ndash269 2006

[21] R S E Keefe T E Goldberg P D Harvey J M Gold M PPoe and L Coughenour ldquoThe Brief Assessment of Cognitionin Schizophrenia reliability sensitivity and comparison with astandard neurocognitive batteryrdquo Schizophrenia Research vol68 no 2-3 pp 283ndash297 2004

[22] G Liu S Zhang Z Cai et al ldquoPICALM gene rs3851179polymorphism contributes to Alzheimerrsquos disease in an Asianpopulationrdquo NeuroMolecular Medicine vol 15 no 2 pp 384ndash388 2013

[23] A H Kim E K Parker V Williamson G O McMichael AH Fanous and V I Vladimirov ldquoExperimental validation ofcandidate schizophrenia gene ZNF804A as target for hsa-miR-137rdquo Schizophrenia Research vol 141 no 1 pp 60ndash64 2012

[24] C Wright J A Turner V D Calhoun and N Perrone-Bizzozero ldquoPotential impact of miR-137 and its targets inschizophreniardquo Frontiers in Genetics vol 4 p 58 2013

[25] M V Frantseva P B Fitzgerald R Chen B Moller MDaigle and Z J Daskalakis ldquoEvidence for impaired long-termpotentiation in schizophrenia and its relationship to motor skillleaningrdquo Cerebral Cortex vol 18 no 5 pp 990ndash996 2008

[26] R A Sewell E B Perry L P Karper et al ldquoClinical significanceof neurological soft signs in schizophrenia factor analysis of theNeurological Evaluation Scalerdquo Schizophrenia Research vol 124no 1ndash3 pp 1ndash12 2010

[27] I Guella A Sequeira B Rollins et al ldquoAnalysis of miR-137expression and rs1625579 in dorsolateral prefrontal cortexrdquoJournal of Psychiatric Research vol 47 no 9 pp 1215ndash1221 2013

[28] M H Willemsen A Valles L A M H Kirkels et al ldquoChro-mosome 1p213 microdeletions comprising DPYD and MIR137are associated with intellectual disabilityrdquo Journal of MedicalGenetics vol 48 no 12 pp 810ndash818 2011

[29] K J Friston ldquoDysfunctional connectivity in schizophreniardquoWorld Psychiatry vol 1 no 2 pp 66ndash71 2002

[30] R Kanai and G Rees ldquoThe structural basis of inter-individualdifferences in human behaviour and cognitionrdquoNature ReviewsNeuroscience vol 12 no 4 pp 231ndash242 2011

[31] G Sun P Ye K Murai et al ldquoMiR-137 forms a regulatoryloop with nuclear receptor TLX and LSD1 in neural stem cellsrdquoNature Communications vol 2 no 1 article 529 2011

[32] K Jiang C Ren and V D Nair ldquoMicroRNA-137 repressesKlf4 and Tbx3 during differentiation of mouse embryonic stemcellsrdquo Stem Cell Research vol 11 no 3 pp 1299ndash1313 2013

[33] H Geekiyanage and C Chan ldquoMicro RNA-137181c regulatesserine palmitoyltransferase and in turn amyloid 120573 novel targetsin sporadic Alzheimerrsquos diseaserdquo Journal of Neuroscience vol 31no 41 pp 14820ndash14830 2011

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


Table 1 The demographic characteristics of schizophrenic patientsand controls

VariablesSchizophrenic

patients Controls Statisticaltests

(119899 = 611) (119899 = 628)Mean age plusmn SD(year) 3556 plusmn 1395 3654 plusmn 1214 119905 = 1331

119875 = 0183Gender 119899 ()

Male 397 (6498) 417 (6640) 1205942 = 0279119875 = 0597Female 214 (3502) 211 (3360)

SD standard deviation

schizophrenia across ethnicities [14ndash18] Recently Guan et al[19] also found that the rs1625579 locus was associated withschizophrenia risk in a Northern Chinese cohort Howeverthey did not report the effects of miR-137 on certain traitsof schizophrenia such as age at onset clinical symptomsand cognitive functions In the present study we conducteda hospital-based case-control study to address this questionin a Southern Chinese Han population and confirmed ourfindings in a meta-analysis with previously published popu-lations Moreover we also evaluated the association betweenmiR-137 polymorphism and the clinical characteristics ofschizophrenia

2 Subjects and Methods

21 Subjects We recruited 611 schizophrenic patients and 628healthy controls from the affiliated hospital of GuangdongMedical College All patients underwent a standardized bat-tery of examinations including family history extensive drugand alcohol assessment physical and neurological exami-nation and laboratory tests to exclude substance-inducedpsychotic disorders or psychosis caused by general medicalcondition The diagnosis was assigned independently by twoexperienced senior psychiatrists based on the Diagnosticand Statistical Manual of Mental Disorders IV (DSM-IV)Psychotic symptoms were evaluated in accordance withstructured interviews for the Positive and Negative SymptomScale (PANSS) The healthy controls were recruited from theMedical Center of the affiliated hospital of Guangdong Med-ical College Based on unstructured interviews participantswho had a personal or family history of major psychiatricdisorders serious somatic illnesses and substance abusewere excluded The patients and controls were comparablein age and sex distribution (Table 1) The study protocol wasapproved by the ethics committee of Guangdong MedicalCollege andwritten informed consent was obtained from theparticipants andor direct relatives

22 DNA Extraction and Genotyping DNA from bloodsamples was extracted using the Blood DNA Kit (TiangenChina) SNP rs1625579 was genotyped using the SNaPshottechnique with polymerase chain reaction (PCR) primers51015840-TTTAGTCAACATTTGCATTTGGAAGC-31015840 and 51015840-CAACAGATTCCAAAGGTCTCTAGTGTGC-31015840 PCR wasperformed in a 20120583L reaction composed of 1 times GC Buffer

30mMMg2+ 03mM dNTPs 1 U of HotStarTaq polymerase(Qiagen Germany) 1120583L of template DNA (each at a finalconcentration of 5ndash10 ng120583L) and 2 120583L of PCR primersAmplification was performed with the following program2min at 95∘C followed by 11 cycles of 94∘C for 20 s 65∘Cplusmn 05∘Ccycle for 40 s and 72∘C for 15min and then 24cycles consisting of 94∘C for 20 s 59∘C for 30 s and 72∘C for15min with a final extension step at 72∘C for 2min Theextension primer was 51015840-TTTTTTTTTTTTTTTTTTTTT-AAACAAGGGAAATGTTAATCACAATTA-31015840The single-nucleotide primer extension reaction was conducted usingthe ABI PRISM SNaPshot Multiplex Kit Protocol (AppliedBiosystems USA) Then 05120583L of the purified single baseextension products was mixed with 9120583L of Hi-Di formamideand 05 120583L of GeneScan-LIZ 120 internal size standard Aftera denaturing step for 2min at 95∘C followed by cooling to 5∘Cthe mixture was further analyzed by capillary electrophoresisusing anABI Prism 3130xl Genetic Analyzer (Applied Biosys-tems USA) The data were analyzed using GeneMapper 41(Applied Biosystems USA)

23 Neurocognitive Function Assessment The Brief Assess-ment of Cognition in Schizophrenia (BACS) assesses thedifferent aspects of cognition found to be important forcognitive impairment in patients with schizophrenia (1)verbal memory measured by List Learning (2) workingmemory measured by the Digit Sequencing Task (3) motorspeed measured by the Token Motor Task (4) verbal fluencyassessed using the Category Instances and Controlled OralWord Association Test (5) reasoning and problem solvingassessed using the Tower of London and (6) attentionand processing speed assessed using Symbol Coding Thebattery of tests requires approximately 30ndash35 minutes tocomplete in patients with schizophrenia and is scored by twopsychologists Further details on the BACS assessment werereported elsewhere by Keefe et al [20 21]

Meta-Analysis The references included in the analysiswere searched using Pubmed (httpwwwncbinlmnihgovpubmed) HighWire Press (httphighwirestanfordedu)China National Knowledge Infrastructure (CNKI httpwwwcnkinet) and Google Scholar (httpscholargooglecom) without any language limitations focusing on thekeywords ldquoschizophreniardquo and ldquomiR-137rdquo or ldquomicroRNA-137rdquoThe literature search was updated on May 10th 2014 Thecriteria for inclusion were as follows association studieswritten in English diagnosis of schizophrenia accordingto standardized criteria such as DSM or ICD-10 case-control studies investigating rs1625579 genotype and allelefrequencies available genotyping method and sufficient datato calculate the odds ratio (OR)with 95confidence intervals(CI) and 119875 values The following were exclusion criteriareviews or abstracts studies which were not relevant to miR-137 gene rs1625579 polymorphism or schizophrenia studieswhich did not report genotype frequencies The flow of thearticle selection process was shown in Figure 1 In total fiveindependent case-control studies were selected [14 16ndash19]Then the following information was extracted from each















PubMed (n = 15)

CNKI (n = 0)









4 Results




119873Genotype 119899 ()

1205942119875

Allele 119899 ()1205942119875


2119875








1205942 = 0070 0791





lowast119875 lt 005










5 Discussion






Study or subgroup

2012

2013

2013

2013

2014

2014

Schizophrenia


ControlWeight

Odds ratioYear

Odds ratio

109 [010 1235]166 [097 285]111 [055 224]153 [054 432]244 [047 1264]394 [018 8406]

284773241144512

811570

328

121

628

63

791532

314

116

623

61

441429

491

510

611

48

431408

472

496

609

48



114 T versus G


3133 2791Total events 3076 2725



1000 151 [104 220]Subtotal (95 CI)

2012

2013

2013

2013

2014

2014

123 [104 145]111 [083 149]123 [081 185]

325501928917119

811570

328

121

63

628

501162

205

76

46

541

441429

491

510

48

611

261111

319

344

39

550


3133 2791Total events 2389 2080



1000 123 [108 139]Subtotal (95 CI)

090 [042 190]


002)

2012

2013

2013

2013

2014

2014

104 [009 1201]115 [056 234]173 [101 297]162 [057 462]254 [049 1316]425 [020 9112]

293214811114512

52219

1200

81

546

48

50205

1162

76

541

46

27338

1132

358

552

39

26319

1111

344

550

39




2446 2146Total events 2389 2080



1000 158 [108 229]Subtotal (95 CI)

00004)

2012

2013

2013

2013

2014

2014

122 [086 173]123 [106 143]109 [085 140]

35

536213

15

162242

3140

656

1256

126

129192

2694

519

1164

107

881020

2858

982

1222

96

69840

2519

791

1159

87





6266 5582Total events 5465 4805



1000 122 [109 136]Subtotal (95 CI)

113 TT versus GG

093 [049 175]

145 [104 202]172 [074 398]

96

104

002 01 1 10 50













Acknowledgments


References










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology















PubMed (n = 15)

CNKI (n = 0)









4 Results




119873Genotype 119899 ()

1205942119875

Allele 119899 ()1205942119875


2119875








1205942 = 0070 0791





lowast119875 lt 005










5 Discussion






Study or subgroup

2012

2013

2013

2013

2014

2014

Schizophrenia


ControlWeight

Odds ratioYear

Odds ratio

109 [010 1235]166 [097 285]111 [055 224]153 [054 432]244 [047 1264]394 [018 8406]

284773241144512

811570

328

121

628

63

791532

314

116

623

61

441429

491

510

611

48

431408

472

496

609

48



114 T versus G


3133 2791Total events 3076 2725



1000 151 [104 220]Subtotal (95 CI)

2012

2013

2013

2013

2014

2014

123 [104 145]111 [083 149]123 [081 185]

325501928917119

811570

328

121

63

628

501162

205

76

46

541

441429

491

510

48

611

261111

319

344

39

550


3133 2791Total events 2389 2080



1000 123 [108 139]Subtotal (95 CI)

090 [042 190]


002)

2012

2013

2013

2013

2014

2014

104 [009 1201]115 [056 234]173 [101 297]162 [057 462]254 [049 1316]425 [020 9112]

293214811114512

52219

1200

81

546

48

50205

1162

76

541

46

27338

1132

358

552

39

26319

1111

344

550

39




2446 2146Total events 2389 2080



1000 158 [108 229]Subtotal (95 CI)

00004)

2012

2013

2013

2013

2014

2014

122 [086 173]123 [106 143]109 [085 140]

35

536213

15

162242

3140

656

1256

126

129192

2694

519

1164

107

881020

2858

982

1222

96

69840

2519

791

1159

87





6266 5582Total events 5465 4805



1000 122 [109 136]Subtotal (95 CI)

113 TT versus GG

093 [049 175]

145 [104 202]172 [074 398]

96

104

002 01 1 10 50













Acknowledgments


References










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



119873Genotype 119899 ()

1205942119875

Allele 119899 ()1205942119875


2119875








1205942 = 0070 0791





lowast119875 lt 005










5 Discussion






Study or subgroup

2012

2013

2013

2013

2014

2014

Schizophrenia


ControlWeight

Odds ratioYear

Odds ratio

109 [010 1235]166 [097 285]111 [055 224]153 [054 432]244 [047 1264]394 [018 8406]

284773241144512

811570

328

121

628

63

791532

314

116

623

61

441429

491

510

611

48

431408

472

496

609

48



114 T versus G


3133 2791Total events 3076 2725



1000 151 [104 220]Subtotal (95 CI)

2012

2013

2013

2013

2014

2014

123 [104 145]111 [083 149]123 [081 185]

325501928917119

811570

328

121

63

628

501162

205

76

46

541

441429

491

510

48

611

261111

319

344

39

550


3133 2791Total events 2389 2080



1000 123 [108 139]Subtotal (95 CI)

090 [042 190]


002)

2012

2013

2013

2013

2014

2014

104 [009 1201]115 [056 234]173 [101 297]162 [057 462]254 [049 1316]425 [020 9112]

293214811114512

52219

1200

81

546

48

50205

1162

76

541

46

27338

1132

358

552

39

26319

1111

344

550

39




2446 2146Total events 2389 2080



1000 158 [108 229]Subtotal (95 CI)

00004)

2012

2013

2013

2013

2014

2014

122 [086 173]123 [106 143]109 [085 140]

35

536213

15

162242

3140

656

1256

126

129192

2694

519

1164

107

881020

2858

982

1222

96

69840

2519

791

1159

87





6266 5582Total events 5465 4805



1000 122 [109 136]Subtotal (95 CI)

113 TT versus GG

093 [049 175]

145 [104 202]172 [074 398]

96

104

002 01 1 10 50













Acknowledgments


References










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




5 Discussion






Study or subgroup

2012

2013

2013

2013

2014

2014

Schizophrenia


ControlWeight

Odds ratioYear

Odds ratio

109 [010 1235]166 [097 285]111 [055 224]153 [054 432]244 [047 1264]394 [018 8406]

284773241144512

811570

328

121

628

63

791532

314

116

623

61

441429

491

510

611

48

431408

472

496

609

48



114 T versus G


3133 2791Total events 3076 2725



1000 151 [104 220]Subtotal (95 CI)

2012

2013

2013

2013

2014

2014

123 [104 145]111 [083 149]123 [081 185]

325501928917119

811570

328

121

63

628

501162

205

76

46

541

441429

491

510

48

611

261111

319

344

39

550


3133 2791Total events 2389 2080



1000 123 [108 139]Subtotal (95 CI)

090 [042 190]


002)

2012

2013

2013

2013

2014

2014

104 [009 1201]115 [056 234]173 [101 297]162 [057 462]254 [049 1316]425 [020 9112]

293214811114512

52219

1200

81

546

48

50205

1162

76

541

46

27338

1132

358

552

39

26319

1111

344

550

39




2446 2146Total events 2389 2080



1000 158 [108 229]Subtotal (95 CI)

00004)

2012

2013

2013

2013

2014

2014

122 [086 173]123 [106 143]109 [085 140]

35

536213

15

162242

3140

656

1256

126

129192

2694

519

1164

107

881020

2858

982

1222

96

69840

2519

791

1159

87





6266 5582Total events 5465 4805



1000 122 [109 136]Subtotal (95 CI)

113 TT versus GG

093 [049 175]

145 [104 202]172 [074 398]

96

104

002 01 1 10 50













Acknowledgments


References










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


Study or subgroup

2012

2013

2013

2013

2014

2014

Schizophrenia


ControlWeight

Odds ratioYear

Odds ratio

109 [010 1235]166 [097 285]111 [055 224]153 [054 432]244 [047 1264]394 [018 8406]

284773241144512

811570

328

121

628

63

791532

314

116

623

61

441429

491

510

611

48

431408

472

496

609

48



114 T versus G


3133 2791Total events 3076 2725



1000 151 [104 220]Subtotal (95 CI)

2012

2013

2013

2013

2014

2014

123 [104 145]111 [083 149]123 [081 185]

325501928917119

811570

328

121

63

628

501162

205

76

46

541

441429

491

510

48

611

261111

319

344

39

550


3133 2791Total events 2389 2080



1000 123 [108 139]Subtotal (95 CI)

090 [042 190]


002)

2012

2013

2013

2013

2014

2014

104 [009 1201]115 [056 234]173 [101 297]162 [057 462]254 [049 1316]425 [020 9112]

293214811114512

52219

1200

81

546

48

50205

1162

76

541

46

27338

1132

358

552

39

26319

1111

344

550

39




2446 2146Total events 2389 2080



1000 158 [108 229]Subtotal (95 CI)

00004)

2012

2013

2013

2013

2014

2014

122 [086 173]123 [106 143]109 [085 140]

35

536213

15

162242

3140

656

1256

126

129192

2694

519

1164

107

881020

2858

982

1222

96

69840

2519

791

1159

87





6266 5582Total events 5465 4805



1000 122 [109 136]Subtotal (95 CI)

113 TT versus GG

093 [049 175]

145 [104 202]172 [074 398]

96

104

002 01 1 10 50













Acknowledgments


References










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology









Acknowledgments


References










































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

























Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

Research Article Association of a miRNA-137 Polymorphism...

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Transcript of Research Article Association of a miRNA-137 Polymorphism...