946
Views & Citations10
Likes & Shares
Schizophrenia is a
multifaceted and multifactorial mental disorder. The aim of the present study
was to analyze the age-related features, biochemical changes, chromosomal
alterations and genetic polymorphisms of schizophrenia subjects. In total, 254
subjects were taken, based on age group (Group I: <40 years, group II: ≥40
years). Random, numerical and structural aberrations, such as supernumerary
markers (47, XXY, +mar, 47, XY, +ace), ploidy, deletions (6q, 21q), inversions
(9p), translocations (t (5, 11) (q25, q31.2)) and duplications (Xp, 7(p15p21)),
were observed in group I and group II subjects. 66 of the 127 in the subtype
category of schizophrenic individuals (51.97%) showed karyotypic abnormalities.
In our study, higher levels of dopamine, thyroid stimulating hormone, cortisol
and blood pressure were observed in the schizophrenia subjects when compared to
controls. Our results showed that three SNPs of NRXN1 gene were significantly associated with schizophrenia (p=
0.017, rs2024513: A > G, p = 0.006, rs13382584: T > C, p = 0.009, and
rs1558852: G > A, p = 0.031). Furthermore, the association of SNP rs2024513
with schizophrenia remained significant after carrying out Bonferroni
correction. In conclusion, our findings suggest that these regions are of interest
for identifying important genes and biomarkers involved in schizophrenia.
Keywords: Schizophrenia, Chromosome aberrations, NRXN1, Dopamine, TSH, Cortisol, Blood Pressure.
INTRODUCTION
Schizophrenia
is a complex neurocognitive disorder, with genetic etiology estimated at
>80%, mainly due to its heritability [1]. Schizophrenia has been categorized
into five different types: (i) paranoid, (ii) disorganized, (iii) catatonic,
(iv) undifferentiated and (v) residual. The global prevalence of schizophrenia
is estimated to be 1-2%. It begins in the late teens to early 20s in males, but
with a five-year delay in onset in females. The diagnostic criteria for this
disease have been established by the Diagnostic and Statistical Manual of
Mental Disorders, 4th edition-Text Revised (DSM IV-TR) [2], mainly stating
exhibition of psychotic symptoms, but no details are available on
deterioration.
Several biological markers have been identified, such as cortisol [3],
metabolic syndrome parameter (BP) and thyroid-stimulating hormone (TSH).
Hypothyroidism and hyperthyroidism are accompanied by various neuropsychiatric
manifestations, such as depression [4], anxiety [5], and psychosis [6].
The co-occurrence of psychiatric and thyroid diseases may be the result
of common biochemical abnormalities [7]. The levels of neurotransmitters
regulated in the brain by reuptake and metabolism affect pituitary function,
leading to reduced TSH levels and an elevated level of dopamine (DA). Higher
basal
Cytogenetic analysis has identified chromosomal aberrations, asserting
the importance of genetic imprinting [14,15]. Earlier studies suggest that
several chromosomes, including 1q, 2p, 3p, 6p, 6q, 7q, 9q, 11q, 13q, 14q, 15q,
22q, and Xp, contain susceptible genes for schizophrenia [14,16]. In addition
to these observations, cases showing the partial trisomy of 5q11-13 [17],
specific translocations such as t(18,21)(p11.1,p11.1) [18], t(1,7)(p22q22) [19]
and t(1, 11)(q42,q14.3) [20], inversions such as inv(9)(p11q13) [21] and
inv(4)(p15q21.3) [22], trisomies of 5p14.1 [23] and deletions at 22q11.1
[17,24] and 5q21-23.1 [25], and sex aneuploidies [26], have been reported in schizophrenic
patients.
In the present study, screening of NRXN1
gene polymorphisms and chromosomal analysis of peripheral blood lymphocytes
were investigated in schizophrenia subjects, with an assessment of the
relationship between the abnormalities found in disease subtype, gender, age at
disease onset and family history. Furthermore, we also investigated the
biochemical relationships resulting in co-occurrence of psychiatric diseases,
by measuring the levels of DA, cortisol, TSH and BP between age-related groups
with age-matched controls and subtypes of schizophrenic patients in a South
Indian population.
MATERIALS AND METHODS
Subject
Patients and Controls
The study groups consisted of 254 samples with 127 schizophrenia
subjects and an equal number of ± 2yrs age-matched controls. Records were
reviewed independently by two diagnostically-trained psychiatrists blind to
family structure, and diagnoses were made according to DSM IV-TR criteria.
Among the 127 schizophrenic cases, the subjects were categorized based on their
age: group I (<40yrs) [n=83, males n= 57 (68.67%), females n=26
(31.33%)] and group II (≥40yrs) [n=44,
males n= 31 (70.45%), females n=13 (29.55%)]. Characteristics of
the patients and controls are listed in Table
1. Pedigree analyses were carried out to visualize the carrier within
families, and to understand the mode of inheritance (paternal and maternal) of
the diseases. Patients with any other known neurological disorders were
excluded.
Patients were
selected from Chaitanya Rehabilitation center, Cochin (Kerala), and from
hospitals in Coimbatore and Chennai (Tamil Nadu) and Bangalore (Karnataka)
during the 2007- 2013 period. The work was carried out in accordance with the
ethical standards laid down in the 1964 Declaration of Helsinki [27], and
written informed consent was obtained from individuals. Healthy controls of similar ethnicity were
selected.
Blood samples
10mL of blood were collected from each participant in 2 sterile tubes
containing EDTA and Heparin by venipuncture from the antecubital vein, and a
follow-up study was conducted. The tubes were analyzed for chemical and
biochemical parameters by transporting at 4ºC. All samples were kept at room
temperature for 24 h prior to processing.
Chromosomal analysis
Cultures of leucocytes were obtained from peripheral blood samples [28]
following standard procedure. 0.5 mL blood was added to 4.5 mL of RPMI 1640
medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 1%
streptomycin-penicillin, 0.2 mL reagent grade phytohemagglutinin (Sigma
Chemicals), and incubated at 37ºC. After 71 h, cultures were treated with 0.1
g/mL colcemid (Gibco Laboratory) to block mitosis. Lymphocytes were harvested
after 72 h by centrifugation (800-1000 rpm). A hypotonic solution of KCl (0.075
M) was added and maintained at 37ºC for 20 min to swell the cells, followed by
Carnoy’s fixative (methanol: acetic acid (3:1)) treatment and dried on a hot
plate (56ºC, 2 min). Three days later, slides were stained using the Trypsin -
Giemsa technique. For the CA analysis, 100 metaphases in first cell cycle were
evaluated per subject under a microscope (100X) to identify numerical and
structural CA.
Mutational analysis
Whole genomic DNA was collected as per kit protocol using a frozen
blood DNA extraction kit (Genei, India). Considering the report by Kirov and
co-workers (10) that microdeletions spanning the promoter and the first exon of
the NRXN1 gene might increase the
risk of developing schizophrenia, three tagSNPs locating the promoter and the
first exon of this gene were selected using dbSNP database
(http://www.ncbi.nlm.nih.gov/SNP) [10,13].
All of the three tag SNPs were genotyped. The information from ABI
Taqman assays and context sequences of three SNPs are given in Table 8. The standard SNP genotyping
assay protocol was performed for polymerase chain reactions (PCRs), which
contained 10ng of DNA, 5μL of 2×TaqMan Universal PCR Master Mix, 0.5μL of 20×
SNP Genotyping Assay Mix and 4.5μL of water, forming a total volume of 10μL.
The conditions of PCR amplification were as follows: 1 enzyme activation step
at 95°C for 10 min, and 40 alternating cycles of denaturation at 92°C for 15s
and re-annealing and extension at 60°C for 60s.
Biochemical Analysis
Estimation of DA
DA was estimated by reference methodology - HPLC with electrochemical
detection [29]. HPLC was performed, fitted with Interface D-7000 IF, dual pump
L-7100 and clinlab digital amperometric detector. Catecholamines kit, HPLC
column, mobile phase 10L and plasma endocrine controls (normal and
experimental) were also used. The HPLC column was connected to the pump, mobile
phase was set at 1 mL/min and the column outlet was attached to the cell inlet
of detector - EC3000. Backpressure was set at 46 bar making the column
dust-free and ideal for HPLC separation. The detector was set at: 560mV,
Filter: 0.05Hz, Cell Type: Passive, Range: ±10 (nA), Offset: 0.00 (nA),
Autozero: Disabled. Base current was +0.13 (nA) only, lower than the permitted
0.3 (nA) making the analysis of DA highly sensitive.
Cortisol analysis
Analysis of plasma cortisol was performed according to Petrowski et al.
[30]. 50μL of low-viscosity saliva supernatant were removed using a
commercially available immunoassay with chemical luminescence detection as
described previously in detail by Dressendörfer et al. [31].
Thyroid-Stimulating Hormone (TSH) analysis
Blood samples were drawn after a 12 h overnight fast. TSH serum level
was determined immediately. For the normal range three different criteria were
used: (1) currently accepted 0.4–5.0 lIU/mL range, (2) 0.3–3.0 lIU/mL range,
proposed by the American Association of Clinical Endocrinology [32], and (3)
0.4–2.5 lIU/mL range, recommended by The National Academy of Clinical
Biochemistry (NACB) [33].
Statistical Analysis
All statistical analyses were performed using SPSS software (version
17) to assess the group statistics for subjects and controls as mean ± SD. For
statistical data inference, the t test for independent variables and ANOVA was
used to compare mean values of the quantitative variables. The comparison and
deviation of genotype frequencies from the expected were examined by the
chi-square test. Multiple regression analysis was performed to determine the
correlation of continuous variables, by using them as dependent variables, with
several independent variables. A significance level of 0.05 was adopted, all
the levels were compared and analyzed for statistical difference. Analysis of
variance was carried out to find the significance.
RESULT
Group comparisons of patient demographics and
clinical profiles
The demographic characteristics of the subjects and control group,
along with sex ratio of 1:8 males to females, are shown in Table 1. The research population consisted of 254 schizophrenic
subjects. The
patients were divided into the following: paranoid, 45 (35.43%), catatonic, 31 (24.40%),
disorganized, 23 (18.11%), residual, 19 (14.97%), undifferentiated, 9 (7.09%).
The mean ± SD age of onset in group I was (24.22 ± 5.09) and group II was
(38.35 ± 12.18). The mean age of group I control and subjects ± SD was [(30.25
± 5.49), (29.98 ± 5.36)], for males [(30.56 ± 5.80), (30.24 ± 5.69)] and for
females [(29.57 ± 4.78), (29.42 ± 4.63)] respectively. Similarly, the mean age
of the group II controls and subjects was [(56.38 ± 10.07), (56.45 ± 9.98)],
for males [(56.90 ± 10.37), (56.90 ± 10.31)], and for females [(55.15 ± 9.61),
(55.38 ± 9.45)] respectively.
In a pedigree analysis of 127 schizophrenic subjects only 73 main
carriers were identified, in which 45 (61.65%) were the paternal carrier and 28
(38.35%) were the maternal carrier.
Karyotyping results
The detailed chromosomal abnormality (CA), age, sex, age at onset,
group, diagnosis, type, family history, and carrier for individual samples were
analyzed and presented in supp.1. Tables
2 & 3 depict the karyotypic results for group I and group II schizophrenic
subjects.
Chromosome abnormalities were found in 57.83 % of group I subjects. The
aberrations were: 3/83 [3.62%] supernumerary markers from chromosome 47,
XXY,+mar, 47, XY,+ace, quadriradial figure, 2/83 [2.40%] ploidy type of
aberrations, 34/83 [40.96%] deletions of 1q32.1, 1q42.2, 9p21.3, 13q, 6p,
9p31.2, 6q, 22q, 13q, 7q, 10p, 11q, 15q, 16p, 2p24.3, 3/83 [3.62%] duplication
of 7q, Xp, 4q, 3/83 [3.62%] translocations of two balanced
der(3)t(1,3)(p11.2,q25), t(5,11)(q25,q31.2), t(5,15), t(8p22-8p21), 3/83
[3.62%] inversions of 9p. Similarly, chromosome abnormality was found in group
II 18/44 (40.90%). The subject aberrations were: 3/44 [6.81%] supernumerary
markers from chromosome quadriradial figure, 13(p+) and 13(ps+), 11/44 [25%]
deletions of 21q, 6p, 9p, 9q, 16p, 1/44 [2.27%] duplication 7(p15p21), 1/44
[2.27%] translocations of two balanced translocation t(5,15), 2/44 [4.54%] and
inversions of 9p.
66 of the 127 subtype category of schizophrenic individuals (51.97%)
displayed karyotypic abnormalities (Table
4). Paranoid type of schizophrenia subjects (n=25) showed chromosomal abnormality (37.87%), aberrations were
47,XX, +21, 46, XY, del1q, 6q, 13q, 6p, 22q, 7q, 11q, 7q, 21q, duplication in
Xp22 and inversion in 9p. Catatonic type of schizophrenia subjects (n=13) showed chromosomal abnormality
(19.70%), where aberrations were +21, 13p+, del 22q,7q,6p,15q,6q,9q, dup 7,
translocation (8p22-8p21), t(5,15). In disorganized type (n=11), the chromosomal abnormality of 16.66% included deletion,
duplication and supernumerary markers. In residual type of schizophrenics (n=11) the chromosomal abnormality
(37.87%) included aberrations such as ploidy, deletion duplication and
inversion 9 and 11.6. Undifferentiated types of subjects showed chromosomal
abnormality of 9.10% with supernumerary markers and deletion aberrations.
Biochemical analysis
Dopamine
The individual plasma DA values obtained from group I and group II
schizophrenia and control subjects are presented in supplement 2. The mean ± SD
plasma DA levels in both group I (29.95 ± 2.61) and group II (31.06 ± 2.78)
were higher than the control groups (Table
5). In the subtypes, the undifferentiated type (35.57 ± 1.81) and paranoid
type of schizophrenia (31.53 ± 4.49) showed higher percentages when compared to
other subtypes (Table 6).
Cortisol
Table 5 presents group I and group II
schizophrenic subjects compared with controls. Group I (6.67 ± 1.80) showed
increased levels of cortisol when compared to group I controls (6.14 ± 0.17)
and similar results were also observed in group II. The subtypes of schizophrenia
indicated increased levels of cortisol in undifferentiated (8.73 ± 0.06),
paranoid (8.48 ± 0.05) and disorganized types of schizophrenia (8.06 ± 0.06).
However, catatonic (4.74 ± 0.04) and residual types of schizophrenia (4.56 ±
0.09) showed lower levels (Table 6).
Thyroid Stimulating Hormone (TSH)
Table 5 illustrates reduced levels of
mean ± SD levels of TSH in group I schizophrenia subjects (1.26 ± 0.86) as
compared to their controls (1.28 ± 0.61). Group II schizophrenic subjects (1.62
± 1.61) showed increased level of TSH when compared with group II controls
(1.46 ± 0.66) and group I schizophrenic subjects. In the subtypes of schizophrenia,
undifferentiated type of schizophrenia (3.72 ± 1.22) showed two times higher values
than the other groups (Table 6).
Blood Pressure (BP)
The mean±SD levels of BP (systolic and diastolic) are listed in Table
5. BP levels were higher in group II (124.36 ± 5.31/81.93 ± 3.73) and group I
(123.40 ± 6.98/82.66 ± 3.22) schizophrenic subjects when compared to their
respective controls, and an increased level was also evident in paranoid type
(127.93 ± 3.16/80.22 ± 16.14) when compared to other subtypes of schizophrenics
(Table 6).
Statistical
analysis
t test analysis
The analysis by t-test among the biochemical parameters such as dopamine, cortisol, thyroid stimulating hormone and blood pressure for the two groups of interest in this study showed significant values among the schizophrenic subjects when compared to the controls. Significant p-value summary was obtained for all parameters except for group I schizophrenic subjects analyzed for thyroid-stimulating hormone. The analysis revealed p=0.0032 for dopamine in group I, p=0.034 for cortisol in group I and p=0.023 for blood pressure observations. Among group II subjects, a statistical significance of p=0.0045 for dopamine, p=0.014 for cortisol, p=0.023 for thyroid stimulating hormone and p=0.043 for blood pressure was recorded.
Statistical t-test analysis however confirmed a significance of p=0.003, p=0.002, p=0.0043 and p=0.02 for dopamine, cortisol, thyroid-stimulating hormone and blood pressure respectively among the subtypes of schizophrenia subjects.
Regression Analysis
Statistical significance was determined for
the dependent and independent variables, in which the schizophrenic subjects
showed significant values in TSH levels when compared to the other groups (Table 7). Regression analysis showed
TSH of group II with Standardized β = 0.058 and p= 0.710, having a significant
effect. Cortisol group II showed standardized β = 0.687 and p= 0.00, DA group
II showed standardized β = 0.579, TSH group I showed standardized β = -0.081
and p= 0.467, cortisol group I showed standardized β = 0.580 and p= 0.00 and DA
group I showed standardized β = 0.332 and p= 0.02, inferring a slight influence
on the TSH levels in group II subjects.
Mutation Analysis
Three SNPs in the NRXN1 gene were genotyped in 127 schizophrenia patients and an equal number of controls. The size of our sample was sufficient to detect a significant difference with a power of more than 90%, assuming an odds ratio (OR) value of AA as 1.7 with a minor allele frequency of 0.1. The genotype distributions of the three SNPs for patients and controls were in Hardy-Weinberg equilibrium (Table 9). Significant differences were found in allele frequencies between patients and controls at three SNPs- rs2024513 (A > G, p = 0.004), rs13382584 (T > C, p = 0.007), and rs1558852 (G > A, p = 0.027). However, the difference in the allele frequencies of rs2024513 alone remained significant after Bonferroni correction. Logistic regression was used to identify whether age influenced the marker-diagnosis effects. However, the age of subjects did not show any significant confounding effects on marker diagnosis association. Furthermore, no association was found between NRXN1 polymorphisms and early-onset schizophrenia. DISCUSSION
Schizophrenia is a seriously debilitating condition that features high on the list of leading causes of lifetime disability. Pathogenesis of schizophrenia has been an ongoing study due to the involvement of genetic factors. To the best of our knowledge, this is the first study for the evaluation of chromosomal alterations and NRXN1 gene polymorphisms compared with biochemical parameters in Indian schizophrenic patients.
Resurgence of interest in gender differences in schizophrenia is a recent research effort aimed at understanding heterogeneity in schizophrenia. Specifically, it is well known that schizophrenia is highly variable in its clinical presentation, and it is possible to identify the distinct etiological subtypes which would likely have a major impact on researchers’ understanding of schizophrenia [34]. This is perhaps due to the fact that the most robust gender difference in schizophrenia is its earlier age of onset in men compared with women [35]. The present study shows the age distribution of the schizophrenic population and age at onset in table 1, similar to the study of Faraone et al. [36] and Szymanski et al. [37].
Some of the chromosome banding which revealed imbalances in earlier studies are 1q21.1, 2p24.3, 3q29, 6p, 7q, 9p21.3, 10p, 11q, 13q,15q11.2,16p1.1,22q and Xp. There are other studies which have also implicated the chromosomal region 11q21-22 as containing genes that increase the liability for schizophrenia. Thus, some balanced translocations at q14.3, q21, q22.3 and q25 sites of chromosome 11 were found in schizophrenia and other psychiatric disorders [38]. Furthermore, our study suggests that different chromosomal regions meet the arbitrarily defined relevance criteria as promising susceptibility genes for schizophrenia, such as deletions at 1q, 7q, 11q and 22q [17,24,39-42], and sex chromosomes such as 47, XXY,+mar, 47,XY,+ace. Interestingly, some similar reports were observed by Toyota et al. [21] and two types of clonal chromosomal aberration: inv (9)(p11q13) and X chromosome aneuploidy is also displayed in group I subjects, according to Toyato et al. [21] and Demirhan et al. [39].
Additionally, plasma DA levels in both group I and group II subjects were higher than in the control groups. Based on earlier studies, analysis of plasma DA in patients showed a significant decrease (p<0.01), which is in agreement with the findings of Kelly & Cooper [43]. However, some workers have also reported no changes in DA [44], which is in agreement with the findings of Yoshida et al. [45]. Among the undifferentiated type of schizophrenic, paranoid type subjects showed higher levels when compared to other subtypes of schizophrenia.
Here, the relationship between hypertension in schizophrenic subjects and metabolic syndrome was observed. Schizophrenic group I & II subjects show higher BP values (≥ 130/85 mm Hg) than in control groups, with mean values of Systolic Blood Pressure (SBP) (124.36 ± 5.31) as well as Diastolic Blood Pressure (DBP) (81.93 ± 3.73). The paranoid type of schizophrenia also showed a higher level (127.93 ± 3.16/80.22 ± 16.14), although a statistically significant difference was observed [46,47].
The comparison of TSH levels among the age groups of the subjects showed significant differences. In this study the samples revealed that the mean serum TSH levels were higher in patients with undifferentiated type of schizophrenia and lower in group I subjects and controls. This may also be explained by the fact that our study sample was not population-based and reflects associations in thyroid dysfunctions. There are reports which suggest that low rates of TSH are observed in schizophrenia patients [48], but in our study we observed a high TSH rate (6.2%).
Ritsner and co-workers [49] reported that serum cortisol ratios in schizophrenic patients were higher than healthy controls. They associated elevated serum cortisol in schizophrenic patients with anxiety, anger, and hostility. In the current study, Groups I and II showed increased levels of cortisol when compared to respective control units, whereas in the subtypes of schizophrenia, an increased level of cortisol was observed in undifferentiated, paranoid and disorganized types of schizophrenia, whereas catatonic and residual types of schizophrenia showed lower levels of cortisol. It has been reported in some studies that elevated serum cortisol is directly proportional to disease duration in patients with schizophrenia and depression [49]. The significant differences between schizophrenic patients, their first-degree relatives and controls, in terms of serum cortisol ratios analyzed in the existing study indicate no significant differences between patients with different types of schizophrenia in terms of cortisol ratios.
NRXN1 and its other members are synaptic neuronal adhesion molecules [9,10]. The deletions, along with any kind of point mutations in the neurexin1 (NRXN1) genes, are coupled with an increased risk of schizophrenia [50]. Thus, in our study we investigated the association of NRXN1 polymorphisms in schizophrenia and healthy control subjects (Table 9). Significant differences were found in allele frequencies between patients and controls at three SNPs (rs2024513, rs13382584, rs1558852). However, only the difference in the allele frequencies of rs2024513 remained significant after the stringent Bonferroni multiple-test. Several previous studies have suggested that the NRXN1 gene might be the susceptibility gene for schizophrenia and other neuro-developmental disorders with rare polymorphisms [13,51]. Thus, schizophrenia has been considered to be genetically complicated, as many susceptibility genes, different genetic markers (SNPs and chromosomal alterations), diversity of genotype and allele distributions may be hypothesized to be allied with this disease.
Thus, the genetic conclusions related with the neurological as well as personality changes allied with the phenotypes will help discover the role of more applicable genes in the pathogenesis of schizophrenia [52].
ACKNOWLEDGMENT
The authors thank the Management of Bharathiar University for providing infrastructure facilities for this research work and the subjects who volunteered to take part in this study.
CONFLICT
OF INTEREST
The authors declare that there are no conflicts of interest.
- Cardno AG, Gottesman II (2000) Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genetics 97: 12-17.
- American Psychiatric Association (2000) Diagnostic, Statistical manual of mental disorders. (4th edn), American Psychiatric Press, Washington DC.
- Carroll BJ, Cassidy F, Naftolowitz D (2007) Pathophysiology of hypercortisolism in depression. Acta Psychiatrica Scandinavica 115: 90-103.
- Trzepacz PT, McCue M, Klein I, Levey GS, Greenhouse JA (1988) psychiatric and neuropsychological study of patients with untreated Graves’ disease. Gen Hosp Psychiatry 10: 49-55.
- Kathol RG, Delahun JW (1986) The relationship of anxiety and depression to symptoms of hyperthyroidism using operational criteria. Gen Hosp Psychiatry 8: 23-28.
- Snabboon T, Khemkha A, Chaiyaumporn C, Lalitanantpong D, Sridama V (2009) Psychosis as the first presentation of hyperthyroidism. Intern Emerg Med 4: 359-360.
- Dunlop BW, Nemeroff CB (2007) The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 64: 327-337.
- Yazici K, Yazici AE, Taneli B (2002) Different neuroendocrine profiles of remitted and nonremitted schizophrenic patients. Prog Neuro-Psychopharmacol Biol Psychiatry 26: 579-584.
- Kim HG, Kishikawa S, Higgins AW, Seong IS, Donovan DJ, et al. (2008) Disruption of neurexin 1 associated with autism spectrum disorder. American J Hum Gen 82: 199-207.
- Kirov G, Rujescu D, Ingason A, Collier DA, O’ Donovan MC, et al. (2009) Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr Bull 35: 851-854.
- Reissner, C, Klose M, Fairless R, Missler M (2008) Mutational analysis of the neurexin/neuroligin complex reveals essential and regulatory components. Proceedings National Acad Sci USA 105: 15124-15129.
- Ikeda M, Aleksic B, Kirov G, Kinoshita Y, Yamanouchi Y, et al. (2010) Copy number variation in schizophrenia in the Japanese population. Biol Psychiatry 67: 283-286.
- Rujescu D, Ingason A, Cichon S, Pietilainen OP, Barnes MR, (2009) Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Gen 18: 988-996.
- Baron M (2001) Genetics of schizophrenia and the new millennium: progress and pitfalls. Am J Hum Gen 68: 299-312.
- Bassett AS (1992) Chromosomal aberrations and schizophrenia. Br J Psychiatry 161: 323-334.
- Chiu YF, McGrath JA, Thornquist MH, Wolyniec PS, Nestadt G, et al. (2002) Genetic heterogeneity in schizophrenia. II. Conditional analyses of affected schizophrenia sibling pairs provide evidence for an interaction between markers on chromosome 8p and 14q. Mol Psychiatry 7: 658-664.
- Bassett AS, Chow EW, Weksberg R (2000) Chromosomal abnormalities and schizophrenia. Am J Med Gen 97: 45-51.
- Smith AB, Peterson P, Wieland J, Moriarty T, DeLisi LE (1996) Chromosome 18 translocation (18,21)(p11.1,p11.1) associated with psychosis in one family. Am J Med Gen 67: 560-563.
- Gordon CT, Krasnewich D, White B, Lenane M, Rapoport JL (1994) Brief report: translocation involving chromosomes 1 and 7 in a boy with childhood-onset schizophrenia. J Autism Devoid Disorde 24: 537-545.
- Di Forti M, Lappin JM, Murray RM (2007) Risk factors for schizophrenia —All roads lead to dopamine. Eur Neuropsychopharmacol 17: S101-S107.
- Toyota T, Shimizu H, Yamada K, Yoshitsugumm K, Meerabux J, et al. (2001) Karyotype analysis of 161 unrelated schizophrenics: no increased rates of X chromosome mosaicism or inv (9), using ethnically matched and age-stratified controls. Schizophr Res 52: 171-179.
- Palmour RM, Miller S, Fielding A, Vekemans M, Ervin FR (1994) A contribution to the differential diagnosis of the ‘‘group of schizophrenia’’: structural abnormality of chromosome 4. J Psychiatry Neurosci 19: 270-277.
- Malaspina D, Warburton D, Amador X, Harris M, Kaufmann CA (1992) Association of schizophrenia and partial trisomy of chromosome 5p: a case report. Schizophr Res 7: 191- 196.
- Arinami T, Ohtsuki T, Takase K, Shimizu H, Yoshikawa T, et al. (2001) Screening for 22q11 deletions in a schizophrenia population. Schizophr Res 52: 167-170.
- Bennett RL, Karayiorgou M, Sobin CA, Norwood TH, Kay M (1997) Identification of an interstitial deletion in an adult female with schizophrenia, mental retardation, and dysmorphic features: further support for a putative schizophrenia susceptibility locus at 5q21-23.1. Am J Hum Gen 61: 1450-1454.
- Kunugi H, Lee KB, Nanko S (1999) Cytogenetic findings in 250 schizophrenics: evidence confirming an excess of the X chromosome aneuploidies and pericentric inversion of chromosome 9. Schizophr Res 40: 43-47.
- WMA (2000) Declaration of Helsinki (2001) Ethical Principles for Medical Research Involving Human Subjects. 52nd WMA General Assembly, Edinburgh, Scotland.
- Moorhead PS, Novell PC, Mellman WJ, Battips DM, Hungerford DA (1960) Chromosome preparation of leukocyte culture from peripheral blood. Exp Cell Res 20: 613–615.
- Westermann J, Hubl W, Kaiser N, Salewski L (2002) Simple rapid and sensitive determination of epinephrine and norepinephrine in urine and plasma by non-competitive enzyme immunoassay, compared with HPLC method. Clin Lab 48: 61-71.
- Petrowski K, Wintermann GB, Kirschbaum C, Bornstein SR (2012) Dissociation between ACTH and cortisol response in DEX –CRH test in patients with panic disorder. Psychoneuroendocrinol 37: 1199-1208.
- Dressendörfer RA, Kirschbaum C, Rohde W (1992) Synthesis of a cortisol-biotin conjugate and evaluation as a tracer in an immunoassay for salivary cortisol measurement. J Steroid Biochem Mol Biol 43: 683-692.
- Baskin HJ, Cobin RH, Duick DS, Gharib H, Guttler RB, et al. (2002) American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract 8: 457-469.
- Baloch Z, Carayon P, Conte-Devolx B (2003) Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 13: 3-126.
- Tsuang MT, Lyons MJ, Faraone SV (1990) Heterogeneity of schizophrenia: Conceptual models and analytic strategies. Br J Psychiatry 156: 17-26.
- Castle DJ, Wessely S, Murray RM (1993) Sex and schizophrenia: effects of diagnostic stringency, and associations with premorbid variables. Br J Psychiatry 162: 658-664.
- Faraone SV, Chen WJ, Goldstein JM, Tsuang MT (1994) Gender differences in age at onset of schizophrenia. Br J Psychiatry 164: 625-629.
- Szymanski S, Lieberman JA, Alvir JM, Mayerhoff D, Loebel A, et al. (1995) Gender differences in onset of illness, treatment response, course, and biologic indexes in first-episode schizophrenic patients. Am J Psychiatry, 152: 698-703.
- Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, et al. (2000) Disruption of two novel genes by a translocation co- segregating with schizophrenia. Hum Mol Gen 9, 1415-1423.
- Demirhan O, Tastemir D (2003) Chromosome aberrations in a schizophrenia population. Schizophr Res 65: 1-7.
- Hercher L, Bruenner G (2008) Living with a child at risk for psychotic illness: the experience of parents coping with 22q11 deletion syndrome: an exploratory study. American J Med Gen 146: 2355-2360.
- Mensah AK, De Luca V, Stachowiak B, Noor A, Windpassinger C, et al. (2007) Molecular analysis of a chromosome 4 inversion segregating in a large schizophrenia kindred from Hong Kong. Schizophr Res 95: 228-335.
- Raedle J, Friedl W, Engels H, Koenig R, Trojan J, et al. (2001) A de novo deletion of chromosome 5q causing familial adenomatous polyposis, dysmorphic features, and mild mental retardation. Am J Gastroenterol l96: 3016-3020.
- Kelly CB, Cooper SJ (1997) Plasma noradrenaline response to electroconvulsive therapy in depressive illness. Br J Psychiatry 171: 182-186.
- Mann JJ (1998) Neurobiological correlates of the antidepressant action of electroconvulsive therapy. J Eng Technol 14: 172-180.
- Yoshida K, Higuchi H, Kamata M, Yoshimoto M, Shimizu T, et al. (1998) Single and repeated electroconvulsive shocks activate dopaminergic and 5-hydroxytryptaminergic neurotransmission in the frontal cortex of rats. Prog Neuro-Psychopharmacol Biol Psychiatry 22: 435-444.
- Henderson DC, Cagliero E, Copeland PM, Borba CP, Evins E, et al. (2005) Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. Arch Gen Psychiatry 62: 19-28.
- Verma AK, Bajaj S, Verma S, Varma A, Meena LP (2013) Study of the association of metabolic syndrome with Schizophrenia in north eastern part of India. International J Med Sci Public Health 2: 583-587.
- Ozerdem A, Tunca Z, Cimrin D, Hidiroglu C, Ergor G (2014) Female vulnerability for thyroid function abnormality in bipolar disorder: role of lithium treatment. Bipolar Disord 16: 72-82.
- Ritsner M, Maayan R, Gibel A, Strous RD, Modai I, et al. (2004) Elevation of the cortisol/dehydroepiandrosterone ratio in schizophrenia patients. Eur Neuro Psycho Pharmacol 14: 267-273.
- Jenkins A, Apud JA, Zhang F, Decot H, Weinberger DR, et al. (2014) Identification of candidate single-nucleotide polymorphisms in NRXN1 related to antipsychotic treatment response in patients with schizophrenia. Neuropsychopharmacol 39: 2170-2178.
- Kirov G, Gumus D, Chen W, Norton N, Georgieva L, Sari M (2008) Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Gen 17: 458-465.
- Cacabelos
R, Cacabelos P, Aliev G (2013) Genomics of schizophrenia and pharmacogenomics of antipsychotic
drugs. Open J Psychiatry 3: 46-139.
-
Table 1 -
Table 2
-
Table 3
-
Table 4
-
Table 5
-
Table 6
-
Table 7
-
Table 8
-
Table 9
-
Table 10
-
Table 11
QUICK LINKS
- SUBMIT MANUSCRIPT
- RECOMMEND THE JOURNAL
-
SUBSCRIBE FOR ALERTS
RELATED JOURNALS
- Journal of Biochemistry and Molecular Medicine (ISSN:2641-6948)
- Food and Nutrition-Current Research (ISSN:2638-1095)
- Journal of Veterinary and Marine Sciences (ISSN: 2689-7830)
- Proteomics and Bioinformatics (ISSN:2641-7561)
- Advances in Nanomedicine and Nanotechnology Research (ISSN: 2688-5476)
- Journal of Genetics and Cell Biology (ISSN:2639-3360)
- Journal of Astronomy and Space Research
