Genes, Brain and Behavior (2010) 9: 695–702
doi: 10.1111/j.1601-183X.2010.00599.x
A genome-wide quantitative trait loci scan of neurocognitive performances in families with schizophrenia Y.-J. Lien†,‡,§ , C.-M. Liu¶,∗∗ , S. V. Faraone††,‡‡ , M. T. Tsuang§§,¶¶,∗∗∗ , H.-G. Hwu†,¶,∗∗ , P.-C. Hsiao‡ and W. J. Chen∗,†,‡,§,¶,∗∗ † Institute of Epidemiology and Research Center for Genes,
Environment and Human Health, College of Public Health, ‡ Genetic Epidemiology Core Laboratory, Division of Genomic Medicine, Research Center for Medical Excellence, § Department of Public Health, College of Public Health, ¶ Department of Psychiatry, College of Medicine and ** National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan, †† Department of Psychiatry and ‡‡ Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA, §§ Department of Psychiatry and ¶¶ The Center for Behavioral Genomics, University of California, San Diego, CA, USA, and *** Harvard Departments of Epidemiology and Psychiatry, Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA, USA *Corresponding author: Dr W. J. Chen, Institute of Epidemiology, College of Public Health, National Taiwan University, 17 Xu-Zhou Road, Taipei 100, Taiwan. E-mail:
[email protected]
Patients with schizophrenia frequently display neurocognitive dysfunction, and genetic studies suggest it to be an endophenotype for schizophrenia. Genetic studies of such traits may thus help elucidate the biological pathways underlying genetic susceptibility to schizophrenia. This study aimed to identify loci influencing neurocognitive performance in schizophrenia. The sample comprised of 1207 affected individuals and 1035 unaffected individuals of Han Chinese ethnicity from 557 sib-pair families co-affected with DSM-IV (Diagnostic and Statistical Manual, Fourth Edition) schizophrenia. Subjects completed a face-to-face semi-structured interview, the continuous performance test (CPT) and the Wisconsin card sorting test (WCST), and were genotyped with 386 microsatellite markers across the genome. A series of autosomal genome-wide multipoint nonparametric quantitative trait loci (QTL) linkage analysis were performed in affected individuals only. Determination of genome-wide empirical significance was performed using 1000 simulated genome scans. One linkage peak attaining genome-wide significance was identified: 12q24.32 for undegraded CPT hit rate [nonparametric linkage z (NPL-Z) scores = 3.32, genome-wide empirical P = 0.03]. This result was higher than the peak linkage signal obtained in the previous genome-wide scan using a dichotomous diagnosis of schizophrenia. The identification of 12q24.32 as a QTL has not been consistently
implicated in previous linkage studies on schizophrenia, which suggests that the analysis of endophenotypes provides additional information from what is seen in analyses that rely on diagnoses. This region with linkage to a particular neurocognitive feature may inform functional hypotheses for further genetic studies for schizophrenia. Keywords: CPT, genetics, linkage analyses, neurocognitive endophenotypes, WCST
Received 3 February 2010, revised 10 May 2010, accepted for publication 13 May 2010
Schizophrenia is a complex disorder in which neurocognitive dysfunction is a core symptom (Joyce & Roiser 2007). Although evidence from family, twin and adoption studies suggests a strong genetic contribution to schizophrenia (Sullivan 2005; Sullivan et al . 2003), the search for susceptibility genes has had equivocal results (Crow 2007; Sullivan et al . 2008). Both genetic and phenotypic heterogeneity of schizophrenia may partly account for the difficulties in the genetic dissection of this disorder. Under these circumstances, examining the genetics of schizophrenia by means of quantitative, neurocognitive endophenotypes (Gottesman & Gould 2003) may be beneficial compared with diagnosisbased genetic studies in several ways. First, neurocognitive features of schizophrenia are likely to reflect more directly the genetic expression affecting brain structure and function than clinical manifestations (Braff et al . 2007; Freedman et al . 1999). Second, a subset of genes that influence a disorder may have greater genetic effects on a particular neurocognitive endophenotype than on the disease per se (Gottesman & Gould 2003; Tsuang 2000). Finally, normally distributed quantitative phenotypes are more informative than dichotomous traits for genomic analyses because they do not rely on arbitrary thresholds (Almasy & Blangero 1998). Sustained attention deficits as measured by the continuous performance test (CPT) (Rosvold et al . 1956) and executive dysfunction as measured by the Wisconsin card sorting test (WCST) (Robinson et al . 1980) are candidate neurocognitive endophenotypes (Gottesman & Gould 2003). Performance on the CPT as well as the WCST is impaired not only in patients with schizophrenia but also in their unaffected relatives (Chen et al . 1998a; Cornblatt & Keilp 1994; Goldberg et al . 1987; Koren et al . 1998; Sitskoorn et al . 2004; Szoke et al . 2005). Nevertheless, unlike the strong evidence of
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familial aggregation found for CPT performance (Chen & Faraone 2000), the magnitude of familial aggregation on the WCST performance is modest at best (Laurent et al . 2000; Szoke et al . 2006). Among different indices in these two tasks, CPT perceptual sensitivity (d ), a summary measure calculated from hit rate and false alarm rate, and WCST perseverative errors and categories achieved have been frequently used as schizophrenia endophenotypes (Allen et al . 2009; Chen & Faraone 2000). These particular indices on the CPT or the WCST were used as a composite profile of neurocognitive performance (Hallmayer et al . 2003, 2005) or part of multivariate traits (Doyle et al . 2008) in genetic linkage studies for psychiatric disorders. However, using selective indices might miss other potentially important endophenotypes, like CPT reaction time (Wang et al . 2007). Moreover, indices from the same test may reflect deficits across multiple cognitive functions. For example, previous studies indicated that individual CPT or WCST indices are differentially associated with different symptom dimension for schizophrenia (Liu et al . 1997; Nieuwenstein et al . 2001; Wang et al . 2007) or schizotypy (Barcelo 1999; Gooding & Tallent 2002; Lacerda et al . 2003). In addition, the brain functions underlying WCST perseverative errors might be different from those underlying nonperseverative errors (Barcelo 1999; Gooding & Tallent 2002; Lacerda et al . 2003). This study aimed to evaluate the genetic linkage evidence for neurocognitive performance by applying a genome-wide quantitative linkage scan in a large sample of families with siblings co-affected with schizophrenia (Faraone et al . 2006). Our hypothesis is that the neurocognitive performances in patients with schizophrenia reflect a latent trait that may partially overlap with the heritable pathophysiology of the disorder. By performing genome-wide scans to these individual quantitative traits, we expected that a greater linkage signal and additional regions might be obtained compared with a dichotomous disease phenotype.
Methods Subjects Participants of this study included patients with schizophrenia and their first-degree relatives recruited from six data collection research centers throughout the nation in the Taiwan Schizophrenia Linkage Study between 1998 and 2002 (Hwu et al . 2005). The large nationwide sample of families with schizophrenia was ascertained on the basis of sib-pairs co-affected with DSM-IV (Diagnostic and Statistical Manual, Fourth Edition) schizophrenia, which included only families of Han Chinese ancestry. The original linkage sample consisted of affected individuals (57 parents and 1150 siblings) and 1035 unaffected individuals (764 parents and 828 siblings) from 557 families (Faraone et al . 2006). All participants provided informed consent, and the study was approved by both the US Department of Health and Human Services and the National Taiwan University Hospital’s Internal Review Board of Human Studies. Best-estimate final diagnoses were made by two board-certified research psychiatrists independently on the basis of all clinical information, including the diagnostic interview for genetic studies (DIGS) (Nurnberger et al . 1994), the family interview for genetic studies (FIGS) (NIMH Genetics Initiative 1992), hospital records and the interviewer’s notes.
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Neurocognitive assessment The CPT procedure has been described in detail elsewhere (Chen et al . 1998a). Briefly, numbers from 0 to 9 were randomly presented for 50 milliseconds each, at a rate of one per second. Each subject undertook two CPT sessions: the undegraded 1–9 tasks and 25% degraded 1–9 tasks. Sensitivity (d ), derived from the hit rate (probability of response to target trials) and false alarm rate (probability of response to nontarget trials), reflects an individual’s ability to discriminate target stimuli from nontarget ones. In addition, the reaction time (i.e. the mean time to respond correctly) for each session was also used for the analyses. For the WCST, we used a computerized version (Lin et al . 2000). Subjects were required to match response cards to the four stimulus cards along one of three dimensions (color, form or number) by pressing one of the 1–4 number keys on the computer keyboard. Subjects were not informed of the correct sorting principle nor were they told when the principle would shift during the test, but they were given feedback (‘Right’ or ‘Wrong’) on the screen after each trial. The testing continued until all 128 cards were sorted. Eight performance indices as described in the WCST manual (Heaton et al . 1993) were used for subsequent analyses: (1) total errors: total numbers of perseverative and nonperseverative errors; (2) nonperseverative errors: numbers of errors that were not perseverative; (3) perseverative errors: numbers of errors that were perseverative, reflecting tendency toward perseveration; (4) perseverative responses: numbers of responses that were perseverative, regardless of whether they were correct or not; (5) categories schieved: numbers of times 10 correct responses in a row were made, reflecting overall success; (6) trials to complete first category: numbers of trials to successfully complete the first category (counted as 129 if no category was completed), reflecting initial conceptual ability; (7) conceptual level response: proportion of consecutive correct responses occurring in runs of 3 or more, reflecting insight into the correct sorting principles; (8) failure to maintain set: number of times subject makes between five and nine correct responses in a row, reflecting efficiency of sorting. The adjusted z scores of the CPT indices were derived by means of standardizing the raw scores with adjustments for sex, age and education against a community sample of 345 individuals (Chen et al . 1998a), whereas adjusted z scores of the WCST with adjustments for sex, age and education were derived for individual against a group of 392 healthy controls (S.-H. Lin, C.-M. Liu, S.-K. Liu, T.J. Hwang, M.H. Hsieh, H.-G. Hwu, and W.J. Chen, unpublished data). We winsorized some CPT or WCST scores as −5 or 5, respectively, because these scores were extremely small (5). In addition to using individual index score of the CPT and the WCST in subsequent analyses, a general cognitive score was also derived as a comparison measure. The ‘general cognitive ability’ (Spearman’s g ) is defined as the first factor score derived through an unrotated principal component analysis (PCA), accounting for around 40% of the variance in performance on diverse cognitive measures, as previously described (Carroll 1997). Accordingly, we performed exploratory factor analyses using PCA as the extraction method, with four-component structure being identified. The first component explained 41% of the total variance of the CPT and WCST indices (eigenvalue = 5.43) and is represented as our general cognitive score.
Statistical analysis Comparisons of CPT and WCST scores The adjusted z scores between the affected individuals and their unaffected relatives were compared by a linear mixed effect model with family treated as a random effect. We used Proc MIXED of the SAS software version 9.1 (SAS Institute, Cary, NC) to adjust for withinfamily correlation. Effect sizes were calculated with the unaffected relatives as the reference group to directly contrast the strength of differential performances for the CPT and the WCST between these two groups.
Quantitative trait locus linkage analyses The original genotyping was performed by the Center for the Inherited Disease Research following the center’s standard genotyping procedures (http://www.cidr.jhmi.edu/protocol.html), with 386 Genes, Brain and Behavior (2010) 9: 695–702
A linkage scan for neurocognition in schizophrenia to the observed maximum NPL-Z noted in a simulated sample (North et al . 2003).
microsatellite markers spaced at an average of 9-cM intervals, and has been described in more detail elsewhere (Faraone et al . 2006). NonMendelian inheritance and excessive recombination events were checked, and erroneous genotypes were removed accordingly. Map distances were based on the Marshfield genetic map (Broman et al . 1998). The data included for this study were collected through the genetic initiative of National Institute of Mental Health (NIMH) for schizophrenia and details about how to access these data can be found at the following Web site: http://zork.wustl.edu/nimh. Two separate genome-wide linkage analyses were conducted. Initially, only affected individuals’ performance scores on the CPT or the WCST were subject to genome-wide quantitative trait loci (QTL) linkage analyses using MERLIN 1.1.2 (Abecasis et al . 2002); that is, any subject without a diagnosis of schizophrenia was coded as ‘missing’ in phenotype. The second genome-wide scan was carried out using all available individuals (including both affected individuals and their unaffected relatives). Nonparametric linkage z (NPL-Z) scores were calculated at all available markers throughout the genome using a nonparametric method to test for allele sharing identical by descent among individuals with similar traits. This method makes no assumption of trait distribution, and we thus used scores without transformation in this study. The Sall statistic was calculated using all relative pairs.
Results The distributions of individual performance indices of the CPT and the WCST by affection status are shown in Table 1. On the basis of the adjusted z scores, both affected and unaffected individuals from families with schizophrenia were poorer than the normal comparisons for all indices, as indicated by decreased correct responses and prolonged reaction times. Furthermore, affected individuals had poorer performance across all the indices on both the CPT and the WCST in comparison with their unaffected relatives, except for WCST failure to maintain set. Meanwhile, medium or large effect sizes between affected individuals and their counterparts were found for several indices on the CPT and the WCST. For example, undegraded and degraded CPT d , undegraded CPT hit rate and WCST failure to maintain set had an absolute value of effect size >0.5. More detailed information on the range and skewness for each neurocognitive performance index is shown in Figure S1. Table 2 shows the summary of those genomic regions where an NPL-Z score of ≥ 2.5 was found for an index on the CPT or the WCST of affected individuals only. For the majority of the indices, the peak linkage signal of individual index was located at only one particular chromosomal region with three
Genome-wide significance level The genome-wide significance level was calculated from 1000 simulations using simulated genomes generated by the genedropping algorithm in MERLIN. Simulated data were based on our original family structure, marker informativeness, spacing and missing data, with phenotypic measurement and affection status being preserved. The genome-wide significance level, represented by the P value, was computed using the conservative P = r /1001, where r is the number of times a NPL-Z score greater than or equal
Table 1: Distribution of adjusted z scores‡ of the CPT and the WCST for families with schizophrenia Affected individuals Variables Undegraded CPT Hit rate False alarm rate d Reaction time (centisecond) Degraded CPT Hit rate False alarm rate d Reaction time (centisecond) WCST Total errors Nonperseverative errors Perseverative errors Perseverative response Categories achieved Conceptual level response Failure to maintain set Trials to complete first category
Unaffected relatives
N
Mean
SD
N
Mean
SD
Group comparison Effect size
984 984 984 984
−1.93∗∗∗ 1.53∗∗∗ −2.35∗∗∗ 1.07∗∗∗
2.02 1.95 1.83 1.39
832 832 832 832
−1.07∗∗∗ 1.03∗∗∗ −1.25∗∗∗ 0.51∗∗∗
1.97 1.79 1.68 1.24
−0.44††† 0.28††† −0.65††† 0.45†††
945 945 945 945
−2.48∗∗∗ 1.18∗∗∗ −2.54∗∗∗ 1.02∗∗∗
1.74 1.84 1.52 1.59
802 802 802 802
−1.42∗∗∗ 0.65∗∗∗ −1.43∗∗∗ 0.57∗∗∗
1.70 1.62 1.49 1.52
−0.62††† 0.33††† −0.74††† 0.10†††
748 748 748 748 748 748 748 748
1.39∗∗∗ 0.44∗∗∗ 1.38∗∗∗ 1.39∗∗∗ −1.00∗∗∗ −1.32∗∗∗ −0.45∗∗∗ 0.93∗∗∗
1.16 1.90 1.79 1.87 0.83 1.09 0.95 1.45
666 666 666 666 666 666 666 666
0.39∗∗∗ −0.07 0.54∗∗∗ 0.57∗∗∗ −0.05 −0.31∗∗∗ −0.45∗∗∗ 0.14∗
1.14 1.94 1.63 1.71 0.83 1.07 1.03 1.41
0.88††† 0.26††† 0.52††† 0.48††† −1.14††† −0.94††† 0.00 0.56†††
‡ Standardized
against a sample of 345 normal comparisons for the CPT and another sample of 392 normal comparisons for the WCST. < 0.05; ∗∗∗ P < 0.001 in comparison with the community norm. ††† P < 0.001 in comparing the affected with the unaffected individuals using the mixed effect model with family as random effect. ∗P
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Lien et al. Table 2: Peak linkage results at each chromosome for each neurocognitive measures in individuals with schizophrenia∗ NPL-Z scores CPT Chromosome Chromosome position (cM) 1 3 6 7 8 10 12 16 19 22
212 216 90 161 103 128 60 125 94 158 150 23 68 36
Markers D1S1660 D1S1647 D3S4542 D3S1744 D6S1056 D7S3061 D8S1477 D8S592 D10S1432 D10S217 D12S2078 D16S748 D19S178 D22S683
Cytogenetic location UH 1q31.1 1q32.1 3p14.1 3q24 6q16.1 7q31.33 8p11.23 8q23.3 10q22.1 10q25.1 12q24.32 16p13.13 19q13.31 22q12.3
UF
UR
WCST DH
DD
PE
PR
CA
TCF 2.82
2.97 2.69
2.57
2.57 3.00 2.80 2.58 2.83 2.80 2.66 3.32 2.56 2.64 2.89
∗ Linkage regions achieving nominal P
≤ 0.005. A genome-wide empirical P value 2.0 (Faraone et al . 2006). This implies that our finding may not rule out the possibility that the locus identified is relevant to variation in cognitive performance rather than
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schizophrenia. Nevertheless, revealing the genetic contribution to such trait in schizophrenia is still important because cognitive deficit is a core symptom for schizophrenia (Joyce & Roiser 2007), and the endophenotypic nature of this deficit may help index underlying genetic liability or vulnerability of the disease. This region has seldom been implicated in previous genetic studies for schizophrenia, whereas in its nearby region, 12q24.31, there appears to have two genes of potential interest to schizophrenia susceptibility. First, the P2RX7 gene is involved in Ca2+ dependent signaling and neurotransmitter release and was associated with bipolar affective disorder (Barden et al . 2006). Second, the eIF2B1 gene is involved in determining oligodendrocyte viability and hence might contribute to the stress-related susceptibility to schizophrenia and bipolar disorder (Carter 2007). These results are in-line with that bipolar affective disorder, and schizophrenia may share some genetic susceptibility factors (Schosser et al . 2004, 2007). Whether this regions confer susceptible genes to both bipolar disorder and schizophrenia warrants further investigation. Unlike CPT indices, our genome-wide linkage scans did not find linkage signals for the WCST indices. This is not surprising, given that several lines of evidence suggest the genetic predisposition to WCST performance is much weaker than that to CPT performance. An elevated recurrence risk ratio for CPT deficits (Chen et al . 1998b; Schurhoff et al . 2004) as well as moderate-to-high heritability (Chen & Faraone 2000; Chen et al . 1998b) was found for nonpsychotic relatives of patients with schizophrenia. Furthermore, a positive association was found between the severity of the CPT deficits and the familial loading for schizophrenia (Tsuang et al . 2006). In contrast, limited familial aggregation was found for WCST performances (Laurent et al . 2000; Szoke et al . 2006). In addition, twin studies indicated that WCST performance was mainly influenced by individualspecific environmental variance rather than genetic variance (Chou et al . 2010; Kremen et al . 2007; Taylor 2007). Caution should be taken when interpreting the results of this study. First, multiple indices from the CPT and WCST were used in the QTL analyses, which raise issues pertaining to multiple testing. The correlated nature of the indices among the CPT or WCST adds further complexity to this problem. Consequently, our results that certain genomic regions were implicated to be associated with variation in neurocognitive traits may be false-positive signals. Second, our greatest linkage signal with genome-wide significance was based on scores of affected individuals only, in which the range of these quantitative measures is limited and may not reflect the distribution of these quantitative measures in unaffected relatives. Whether there are regions other than those found in this study warrants further investigation. Third, the resolution of genome-wide linkage studies for gene detection is limited as compared with the genome-wide association studies. Nevertheless, genome-wide linkage studies can be more powerful for the detection of the genetic effects in cases such as loci with multiple rare pathogenic mutations in different families or several different susceptibility loci in the same region (Holmans et al . 2009; Ng et al . 2009). Based on current findings, further studies using high-density markers or deep resequencing methods
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may help identify genetic variants involved in schizophrenia susceptibility. In summary, our QTL genome-wide scans identified 12q24.32 as a novel linkage region for conferring susceptibility to sustained attention deficit in patients with schizophrenia as reflected in the undegraded CPT hit rate. There are some known genes within this region that may be associated with susceptibility to both schizophrenia and bipolar disorder. Our results may inform functional hypotheses for possible biological mechanisms underlying the genetic liability of schizophrenia.
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Tzung-Jeng Hwang, Shi K. Liu, Ching-Jui Chang, Hung-Jung Chang, Hai Ho, Ping-Ju Chang, Shi-Chin Guo, Hsien-Yuan Lane, Su-Kuan Lin, Fu-Chuan Wei, and Joseph J and Cheng, and Miss Shih-Wei Lin and Drs Hui-Chun Tsuang and Sheng-Hsiang Lin for their help in compiling relevant data.
Supporting Information Acknowledgments This study was supported by grants from the National Health Research Institutes, Taiwan (DOH 88-HR-825; NHRI-GTEX89P825P; NHRI-EX90-8825PP; NHRI-EX91, 92, 93-9113PP; NHRI-EX95, 96, 97, 98-9511PP) and National Science Council, Taiwan (NSC 96-2628-B-002-066-MY2 and NSC98-2314-B-002125-MY3), US National Institute of Mental Health grant 1R01MH-59624-01 and NTU grant 97HP0023 and 97HP0071. The authors thank other participants in the Taiwan Schizophrenia Linkage Study who helped in the recruitment and evaluation of patients with schizophrenia, including Drs Ming-Hsien Hsieh,
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Additional Supporting Information may be found in the online version of this article: Figure S1. Distribution of adjusted z scores of the CPT and the WCST for the affected and unaffected individuals, respectively, in the families of patients with schizophrenia. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer-reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.
Genes, Brain and Behavior (2010) 9: 695–702
