Chih-Min Liu

Frequency-specific alternations in the amplitude of low-frequency fluctuations in schizophrenia

Schizophrenia has been associated with abnormal task‐related brain activation in sensory and motor regions as well as social cognition network. Recently, two studies investigated temporal correlation between resting‐state functional magnetic resonance imaging (R‐fMRI) low‐frequency oscillations (LFOs) in schizophrenia but reported mixed results. This may be due to the different frequency bands used in these studies. Here we utilized R‐fMRI to measure the amplitude of low‐frequency fluctuations (ALFF) and fractional ALFF (fALFF) in three different frequency bands (slow‐5: 0.01–0.027 Hz; slow‐4: 0.027–0.08 Hz; and typical band: 0.01–0.08 Hz) in 69 patients with schizophrenia and 62 healthy controls. We showed that there were significant differences in ALFF/fALFF between the two bands (slow‐5 and slow‐4) in regions including basal ganglia, midbrain, and ventromedial prefrontal cortex. Importantly, we also identified significant interaction between frequency bands and groups in inferior occipital gyrus, precunus, and thalamus. The results suggest that the abnormalities of LFOs in schizophrenia is dependent on the frequency band and suggest that future studies should take the different frequency bands into account when measure intrinsic brain activity. Hum Brain Mapp 35:627–637, 2014.

A single nucleotide polymorphism fine mapping study of chromosome 1q42.1 reveals the vulnerability genes for schizophrenia, GNPAT and DISC1 : Association with impairment of sustained attention

BACKGROUND The marker D1S251 of chromosome 1q42.1 showed significant association with schizophrenia in a Taiwanese sample. We used single nucleotide polymorphism (SNP) fine mapping to search for the vulnerability genes of schizophrenia. METHODS We selected 120 SNPs covering 1 Mb around D1S251 from the public database. These selected SNPs were initially validated if allele frequency was >10%. Forty-seven validated SNPs were genotyped in 102 families with at least 2 siblings affected with schizophrenia. RESULTS Two SNP blocks showed significant association with schizophrenia. Block 1 (five-SNP), located between intron 2 and intron 13 of the glyceronephosphate O-acyltransferase (GNPAT) gene, showed the most significant associations using single-locus TDT (z = -2.07, p = .038, df = 1) and haplotype association analyses (z = -1.99, p = .046, df = 1). Block 2 (two-SNP), located between intron 4 and intron 5 of the disrupted-in-schizophrenia 1 (DISC1) gene, also showed the most significant results in both the single-locus (z = -3.22, p = .0013, df = 1) and haplotype association analyses (z = 3.35, p = .0008, df = 1). The association of the DISC1 gene with schizophrenia was mainly in the patient group with sustained attention deficits as assessed by the Continuous Performance Test. CONCLUSIONS Chromosome 1q42.1 harbors GNPAT and DISC1 as candidate genes for schizophrenia, and DISC1 is associated with sustained attention deficits.

More evidence supports the association of PPP3CC with schizophrenia

Calcineurin is a calcium/calmodulin-dependent protein phosphatase composed of two subunits, a regulatory subunit of calcineurin B (CNB) and a catalytic subunit of calcineurin A (CNA). PPP3CC is the γ isoform of CNA located at the chromosome 8p21.3 region. To evaluate the association between PPP3CC and schizophrenia in the Taiwanese population, 10 single nucleotide polymorphism (SNP) markers across the gene were genotyped by the method of MALDI-TOF in 218 schizophrenia families with at least two affected siblings. One SNP (rs2272080) located around the exon 1 untranslated region was nominally associated with schizophrenia (P=0.024) and significantly associated with the expression of PPP3CC in lymphoblast cell line; the TT and TG genotype had significantly higher relative expression levels than the GG genotype (P=0.0012 and 0.015, respectively). In further endophenotype stratification, the single locus of rs2272080 and the haplotypes of both two-SNP haplotype (rs7833266–rs2272080) and seven-SNP haplotype (rs2461491–rs2469758–rs2461489–rs2469770–rs2449340–rs1482337–rs2252471) showed significant associations with the subgroup of schizophrenia with deficits of the sustained attention as tested by the continuous performance test (CPT, P<0.05) and the executive functioning as tested by the Wisconsin Card Sorting Test (WCST, P<0.05). The results suggest that PPP3CC gene may be a true susceptibility gene for schizophrenia.

No association of G72 and d-amino acid oxidase genes with schizophrenia

The genes of D-amino acid oxidase (DAAO) activator (DAOA or G72; 13q34) and DAAO (12q24) have been suggested as candidate genes and involved in the N-methyl-D-aspartate receptor regulation pathway for schizophrenia. In order to evaluate the potential association of these two genes with schizophrenia in a Taiwanese sample, three single nucleotide polymorphisms (SNPs) for DAAO (rs2111902, rs3918346, rs3741775) and eleven SNPs for G72 (rs3916965, rs3916966, rs3916967, rs2391191, rs3916968, rs947267, rs778294, rs3916970, rs3916971, rs778293, rs3918342) were genotyped by the MALDI-TOF mass spectrometry method in 218 families (864 individuals) containing at least two siblings affected with schizophrenia. In SNP-based single locus association analyses, neither G72 nor DAAO showed significant association with schizophrenia. Additionally, a three-SNP haplotype in DAAO, and a four-SNP as well as a two-SNP haplotype in G72, showed no significant associations with schizophrenia. These results suggest that the DAAO and G72 genes are not susceptibility genes for schizophrenia in a Taiwanese sample.

Neuregulin 1 gene and variations in perceptual aberration of schizotypal personality in adolescents

BACKGROUND We test the hypothesis that the neuregulin 1 (NRG1 ) gene at chromosome 8p22-p12, which has been implicated as a susceptibility gene to schizophrenia, is associated with variations in schizotypal personality in non-clinical populations. METHOD A randomly selected sample of 905 adolescents were assessed for their personality features using the Perceptual Aberration Scale (PAS) and the Schizotypal Personality Questionnaire (SPQ) and genotyped for three single nucleotide polymorphisms (SNP8NRG221533, rs3924999, and rs2954041) at the NRG1 gene. Relations between the three genetic variants and continuous schizotypal personality scores were evaluated using ANOVA for single-locus analyses and haplotype trend regression test for multi-locus analyses. RESULTS Single locus analysis showed that the A allele of rs3924999, a functional polymorphism in exon 2, had the largest effect size and exhibited a prominent allele-dose trend effect for the PAS score. Haplotype analyses using the haplotype trend regression test indicated that the A allele of rs3924999 was mainly responsible for the association with the PAS but not with the SPQ or its three factors, and the magnitude of significance was not strengthened by the combination of this allele with adjacent locus. CONCLUSIONS Our study provides the first evidence for the association of NRG1 with schizotypal personality and indicates a possible role of NRG1 in the genetic etiology of schizophrenia through perceptual aberrations.

Genome-wide association study of treatment refractory schizophrenia in Han Chinese.

We report the first genome-wide association study of a joint analysis using 795 Han Chinese individuals with treatment-refractory schizophrenia (TRS) and 806 controls. Three loci showed suggestive significant association with TRS were identified. These loci include: rs10218843 (P = 3.04×10−7) and rs11265461 (P = 1.94×10−7) are adjacent to signaling lymphocytic activation molecule family member 1 (SLAMF1); rs4699030 (P = 1.94×10−6) and rs230529 (P = 1.74×10−7) are located in the gene nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); and rs13049286 (P = 3.05×10−5) and rs3827219 (P = 1.66×10−5) fall in receptor-interacting serine/threonine-protein kinase 4 (RIPK4). One isolated single nucleotide polymorphism (SNP), rs739617 (P = 3.87×10−5) was also identified to be associated with TRS. The -94delATTG allele (rs28362691) located in the promoter region of NFKB1 was identified by resequencing and was found to associate with TRS (P = 4.85×10−6). The promoter assay demonstrated that the -94delATTG allele had a significant lower promoter activity than the -94insATTG allele in the SH-SY5Y cells. This study suggests that rs28362691 in NFKB1 might be involved in the development of TRS.

Symptom patterns and subgrouping of schizophrenic patients: significance of negative symptoms assessed on admission

This study subgroups schizophrenic patients based on symptoms assessed on admission and examines the validity of the subgrouping using follow-up data and other clinical outcome variables. Schizophrenic patients (n=163) from consecutive admission received ratings on the positive and negative syndrome scale (PANSS) on admission and during a 1-year follow-up course. An exploratory graphic analysis on the admission PANSS derived four symptom dimensions: negative symptoms, disorganized thought, hostility/excitement and delusions/hallucinations. This yielded two subgroups of patients on admission, a group with marked negative (GWNEG) and a group without marked negative (GONEG) symptoms. Compared with the GONEG, the GWNEG had a poorer recovery rate, more impairment in attention, a slower response of the delusion/hallucination symptoms to neuroleptic treatment and a longer duration of index hospitalization. At a one-year follow-up, the GWNEG assessed on admission had persistently higher scores on the negative symptom and disorganized thought syndromes, less relapse rate, a shorter duration on job, as well as worse social functioning than the GONEG. Thus, the GONEG might comprise patients having a pure paranoid syndrome with quick and better treatment response, while the GWNEG comprises patients with the blunt-disorganization syndrome having a poorer outcome.

Taiwan schizophrenia linkage study: The field study

One possible reason of the inconsistent results of linkage analyses of schizophrenia, a complex disorder, was mainly due to the small sample size of studies. This Taiwan Schizophrenia Linkage Study (TSLS) was designed to collect a large family sample with at least two affected siblings of a single ethnicity. The 17.6 millions of Taiwanese Chinese, age over 15, was the sample population, and 78 psychiatric hospitals or health centers participated in this TSLS program. Before data collection started, every study subject signed the informed consent. The ascertainment protocol for data collection included blood sample, structured Diagnostic Interview for Genetic Studies (DIGS), Structured Interview for Schizotypy (SIS), scales for assessment of positive and negative symptoms (SAPS, SANS), and continuous performance test (CPT), Wisconsin card sort test (WCST) of neuropsychological functions. We have contacted 831 families for this study and 607 families, comprised 2,490 subjects, were successfully recruited. The recruitment rate was 38.4% from the estimated total of 1,582 families with at least two affected siblings. These collected family samples were fairly evenly distributed all over Taiwan. Those 2,490 study subjects (1,283 male, 1,117 female) comprised 1,568 siblings (mean age 35.7 years old) and 922 parents (mean age 63.6 years old). Of these 1,568 siblings, 1,258 (80.2%) were affected (male 795, female 463), and the mean age of onset was 22.6 years old. Among 922 parents, 65 were affected (male 14, female 51) and the age of onset was 33.1 years old. This TSLS demonstrated a successful establishment of an efficient research infrastructure to collect a large nation‐wise sample of schizophrenic family for genetic linkage study.

RASD2, MYH9, and CACNG2 Genes at Chromosome 22q12 Associated with the Subgroup of Schizophrenia with Non-Deficit in Sustained Attention and Executive Function

BACKGROUND In a previous linkage study of schizophrenia that included Taiwanese samples, the marker D22S278 (22q12.3) was significantly linked to schizophrenia (p = .001). METHODS We conducted fine mapping of the implicated genomic region, with 47 validated single nucleotide polymorphism (SNP) markers around 1 Mb of D22S278, in a Taiwanese sample of 218 pedigrees with at least 2 siblings affected with schizophrenia. We examined the association of these SNPs and their haplotypes with schizophrenia and with subgroups defined by the presence and absence of deficits in sustained attention as assessed by undegraded and degraded continuous performance tests (CPTs). We also examined subgroups defined by deficits in categories achieved in the Wisconsin Card Sort Test (WCST). RESULTS Three of five candidate vulnerability genes (RASD2, APOL5, MYH9, EIF3S7, and CACNG2), which had marginally significant associations with schizophrenia, had significant associations with schizophrenic patients who did not have deficits in sustained attention on the undegraded CPT (RASD2 gene SNP rs736212; p = .0008 with single locus analysis) and the degraded CPT (MYH9 gene haplotype 1-1-1-1 of SNP rs3752463 - rs1557540 - rs713839 - rs739097; p = .0059 with haplotype analysis). We also found a significant association for patients who showed no deficits in executive function as measured by categories achieved in the WCST (CACNG2 gene haplotype 2-1-1-1 of SNP rs2267360 - rs140526 - rs1883987 - rs916269; p = .0163 with haplotype analysis). CONCLUSIONS The genes RASD2, MYH9, and CACNG2 might be vulnerability genes for neuropsychologically defined subgroups of schizophrenic patients.

Frequency Dependent Alterations in Regional Homogeneity of Baseline Brain Activity in Schizophrenia

Low frequency oscillations are essential in cognitive function impairment in schizophrenia. While functional connectivity can reveal the synchronization between distant brain regions, the regional abnormalities in task-independent baseline brain activity are less clear, especially in specific frequency bands. Here, we used a regional homogeneity (ReHo) method combined with resting-state functional magnetic resonance imaging to investigate low frequency spontaneous neural activity in the three different frequency bands (slow-5∶0.01–0.027 Hz; slow-4∶0.027–0.08 Hz; and typical band: 0.01–0.08 Hz) in 69 patients with schizophrenia and 62 healthy controls. Compared with controls, schizophrenia patients exhibited decreased ReHo in the precentral gyrus, middle occipital gyrus, and posterior insula, whereas increased ReHo in the medial prefrontal cortex and anterior insula. Significant differences in ReHo between the two bands were found in fusiform gyrus and superior frontal gyrus (slow-4> slow-5), and in basal ganglia, parahippocampus, and dorsal middle prefrontal gyrus (slow-5> slow-4). Importantly, we identified significant interaction between frequency bands and groups in the inferior occipital gyrus and caudate body. This study demonstrates that ReHo changes in schizophrenia are widespread and frequency dependent.