Schizophrenia in the genetic era: a review from development history, clinical features and genomic research approaches to insights of susceptibility genes.

Schizophrenia is a devastating neuropsychiatric disorder affecting 1% of the world population and ranks as one of the disorders providing the most severe burden for society. Schizophrenia etiology remains obscure involving multi-risk factors, such as genetic, environmental, nutritional, and developmental factors. Complex interactions of genetic and environmental factors have been implicated in the etiology of schizophrenia. This review provides an overview of the historical origins, pathophysiological mechanisms, diagnosis, clinical symptoms and corresponding treatment of schizophrenia. In addition, as schizophrenia is a polygenic, genetic disorder caused by the combined action of multiple micro-effective genes, we further detail several approaches, such as candidate gene association study (CGAS) and genome-wide association study (GWAS), which are commonly used in schizophrenia genomics studies. A number of GWASs about schizophrenia have been performed with the hope to identify novel, consistent and influential risk genetic factors. Finally, some schizophrenia susceptibility genes have been identified and reported in recent years and their biological functions are also listed. This review may serve as a summary of past research on schizophrenia genomics and susceptibility genes (NRG1, DISC1, RELN, BDNF, MSI2), which may point the way to future schizophrenia genetics research. In addition, depending on the above discovery of susceptibility genes and their exact function, the development and application of antipsychotic drugs will be promoted in the future.

The genetics of incontinence: A scoping review.

The genetic causes underlying incontinence in both children and adults have begun to be unravelled during the last decades. The aim of this scoping review is to synthesize current knowledge on the genetics of childhood and adult urinary and faecal incontinence, identify similarities between different incontinence subgroups, and identify knowledge gaps to aid future research. PRISMA-ScR was used, and 76 studies were included. Early epidemiological family and twin studies suggest high heritability of incontinence. Linkage studies provide evidence for the existence of rare genetic variants; however, these variants have not been identified. Later candidate gene association studies and recent genome-wide association studies provide the first preliminary evidence that common risk variants also play a role. The genetics of incontinence in children and adults has predominantly been studied separately, but this review identifies for the first time the endothelin system as a potential common pathophysiological pathway. Overall, these findings strengthen the hypothesis that genetic variants play a prominent role in the pathogenesis of incontinence. Future research should include hypothesis-free studies of rare and common variants in large well-characterized cohorts with incontinence. Studies should include different age groups and ethnicities and both sexes to fully reveal the genetics of incontinence.

A Large-Scale Candidate-Gene Association Mapping for Drought Tolerance and Agronomic Traits in Sugarcane.

Dissection of the genetic loci controlling drought tolerance traits with a complex genetic inheritance is important for drought-tolerant sugarcane improvement. In this study, we conducted a large-scale candidate gene association study of 649 candidate genes in a sugarcane diversity panel to identify genetic variants underlying agronomic traits and drought tolerance indices evaluated in plant cane and ratoon cane under water-stressed (WS) and non-stressed (NS) environments. We identified 197 significant marker-trait associations (MTAs) in 141 candidate genes associated with 18 evaluated traits with the Bonferroni correction threshold (α = 0.05). Out of the total, 95 MTAs in 78 candidate genes and 62 MTAs in 58 candidate genes were detected under NS and WS conditions, respectively. Most MTAs were found only in specific water regimes and crop seasons. These MTAs explained 7.93-30.52% of phenotypic variation. Association mapping results revealed that 34, 59, and 104 MTAs involved physiological and molecular adaptation, phytohormone metabolism, and drought-inducible genes. They identified 19 pleiotropic genes associated with more than one trait and many genes related to drought tolerance indices. The genetic and genomic resources identified in this study will enable the combining of yield-related traits and sugar-related traits with agronomic value to optimize the yield of sugarcane cultivars grown under drought-stressed and non-stressed environments.

Genetic associations with resilience to potentially traumatic events and vantage sensitivity to social support.

INTRODUCTION: Stress responses and mental health outcomes greatly vary when individuals are exposed to potentially traumatic events (PTEs). The Differential Susceptibility Model (DSM) (Pluess, 2015) suggests individual differences in stress responses are influenced by gene-environment interactions, with genes conferring reactivity. While individuals can be resilient (or vulnerable) to PTEs, they can also have vantage sensitivity (or resistance) to social support. This study examined whether selected genotypes moderated the effect of PTEs and social support on mental health. METHODS: This cross-sectional candidate gene study included 450 college students (M age = 20.4, 79.3 % women) who provided buccal cells for genotyping and completed measures of psychosocial variables. DNA was genotyped for 12 genetic variants. RESULTS: Hierarchical regression revealed that the Mental Health Inventory (MHI) was associated with the Trauma History Questionnaire (THQ), rs1800795 in IL-6, and THQ × rs1800795 [R2 = 0.10, F(3, 418) = 15.68, p < .01]. The MHI was associated with the Social Support Survey (SSS), rs4680 in COMT, and SSS × rs4680 [R2 = 0.24, F(3, 429) = 44.19, p < .01]. Only THQ and SSS survived multiple testing corrections. DISCUSSION: Findings partially support the DSM that the G/G genotype of rs1800795 in IL-6 is associated with resilience to PTEs, and the Met/Met genotype of rs4680 in COMT is associated with vantage sensitivity to social support. Limitations include cross-sectional design, limited PTE measurement, small convenience sample, and noncorrection for multiple significance test. Clinicians need to view resilience holistically and understand resilience is associated with psychosocial and genetic factors.

Combined GWAS and QTL analysis for dissecting the genetic architecture of kernel test weight in maize.

Kernel weight in a unit volume is referred to as kernel test weight (KTW) that directly reflects maize (Zea mays L.) grain quality. In this study, an inter-mated B73 × Mo17 (IBM) Syn10 doubled haploid (DH) population and an association panel were used to identify loci responsible for KTW of maize across multiple environments. A total of 18 significant KTW-related single-nucleotide polymorphisms (SNPs) were identified using genome-wide association study (GWAS); they were closely linked to 12 candidate genes. In the IBM Syn10 DH population, linkage analysis detected 19 common quantitative trait loci (QTL), five of which were repeatedly detected among multiple environments. Several verified genes that regulate maize seed development were found in the confidence intervals of the mapped QTL and the LD regions of GWAS, such as ZmYUC1, BAP2, ZmTCRR-1, dek36 and ZmSWEET4c. Combined QTL mapping and GWAS identified one significant SNP that was co-identified in the both populations. Based on the co-localized SNP across the both populations, 17 candidate genes were identified. Of them, Zm00001d044075, Zm00001d044086, and Zm00001d044081 were further identified by candidate gene association study for KTW. Zm00001d044081 encodes homeobox-leucine zipper protein ATHB-4, which has been demonstrated to control apical embryo development in Arabidopsis. Our findings provided insights into the mechanism underlying maize KTW and contributed to the application of molecular-assisted selection of high KTW breeding in maize.

Osteopontin promoter polymorphisms and risk of urolithiasis: a candidate gene association and meta-analysis study.

BACKGROUND: Urolithiasis is a worldwide urological problem with significant contribution of genetic factors. Pakistan, which resides within the Afro-Asian stone belt, has a high reported prevalence (12%) of urolithiasis. Osteopontin (SPP1) is a urinary macromolecule with a suggested critical role in modulating renal stone formation, genetic polymorphisms of which may determine individual risk of developing urolithiasis. However, results of previous studies regarding SPP1 polymorphisms and susceptibility to urolithiasis have apparent inconsistencies with no data available for local population. METHODS: A total of 235 urolithiasis patients and 243 healthy controls, all of Pakistani ancestry, underwent genotyping for six SPP1 genetic polymorphisms in an effort to investigate potential association with urolithiasis using indigenous candidate gene association study design. Further, a comprehensive meta-analysis following a systematic literature search was also done to ascertain an evidence based account of any existent association regarding SPP1 promoter polymorphisms and risk of developing urolithiasis. RESULTS: Three SPP1 promoter polymorphisms, rs2853744:G > T, rs11730582:T > C and rs11439060:delG>G, were found to be significantly associated with risk of urolithiasis in indigenous genetic association study (OR = 3.14; p = 0.006, OR = 1.78; p = 0.006 and OR = 1.60; p = 0.012, respectively). We also observed a 1.68-fold positive association of a tri-allelic haplotype of these SPP1 promoter polymorphisms (G-C-dG) with risk of urolithiasis (OR = 1.68; p = 0.0079). However, no association was evident when data were stratified according to gender, age at first presentation, stone recurrence, stone multiplicity, parental consanguinity and family history of urolithiasis. The overall results from meta-analysis, which included 4 studies, suggested a significant association of SPP1 rs2853744:G > T polymorphism with susceptibility of urolithiasis (OR = 1.37; p = 0.004), but not for other SPP1 polymorphic variants analyzed. CONCLUSIONS: In conclusion, we report significant association of 3 SPP1 polymorphisms with urolithiasis for the first time from South Asia, however, this association persisted only for SPP1 rs2853744:G > T polymorphism after meta-analysis of pooled studies. Further studies with a larger sample size will be required to validate this association and assess any potential usefulness in diagnosis and prognosis of renal stone disease.

Lessons and implications from association studies and post-GWAS analyses of cervical cancer.

Cervical cancer has a heritable genetic component. A large number of genetic associations with cervical cancer have been reported in hypothesis-driven candidate gene studies, but many of these results are either inconsistent or have failed to be independently replicated. Genome-wide association studies (GWAS) have identified additional susceptibility loci previously not implicated in cervical cancer development, highlighting the power of genome-wide unbiased association analyses. Post-GWAS analyses including pathway-based analysis and functional characterization of associated variants have provided new insights into the pathogenesis of cervical cancer. In this review we summarize findings from candidate gene association studies, GWAS, and post-GWAS analyses of cervical cancer. We also discuss gaps in our understanding, possible clinical implications of the findings, and lessons for studies of other complex diseases.

Genetic variation of the growth hormone secretagogue receptor gene is associated with alcohol use disorders identification test scores and smoking.

The multifaceted gut-brain peptide ghrelin and its receptor (GHSR-1a) are implicated in mechanisms regulating not only the energy balance but also the reward circuitry. In our pre-clinical models, we have shown that ghrelin increases whereas GHSR-1a antagonists decrease alcohol consumption and the motivation to consume alcohol in rodents. Moreover, ghrelin signaling is required for the rewarding properties of addictive drugs including alcohol and nicotine in rodents. Given the hereditary component underlying addictive behaviors and disorders, we sought to investigate whether single nucleotide polymorphisms (SNPs) located in the pre-proghrelin gene (GHRL) and GHSR-1a gene (GHSR) are associated with alcohol use, measured by the alcohol use disorders identification test (AUDIT) and smoking. Two SNPs located in GHRL, rs4684677 (Gln90Leu) and rs696217 (Leu72Met), and one in GHSR, rs2948694, were genotyped in a subset (n = 4161) of a Finnish population-based cohort, the Genetics of Sexuality and Aggression project. The effect of these SNPs on AUDIT scores and smoking was investigated using linear and logistic regressions, respectively. We found that the minor allele of the rs2948694 SNP was nominally associated with higher AUDIT scores (P = 0.0204, recessive model) and smoking (P = 0.0002, dominant model). Furthermore, post hoc analyses showed that this risk allele was also associated with increased likelihood of having high level of alcohol problems as determined by AUDIT scores ≥ 16 (P = 0.0043, recessive model). These convergent findings lend further support for the hypothesized involvement of ghrelin signaling in addictive disorders.

Focused screening of a panel of cancer-related genetic polymorphisms reveals new susceptibility loci for pediatric acute lymphoblastic leukemia.

BACKGROUND: A genetic predisposition to acute lymphoblastic leukemia (ALL) in childhood is well established. Currently known risk loci, however, explain only one third of the estimated total risk related to common genetic variations. PROCEDURE: We genotyped 1,421 polymorphisms in 407 candidate genes from the SNP500Cancer database (National Cancer Institute) using the Illumina Cancer SNP Panel. We investigated 78 cases (aged 0-19 years at diagnosis, and mixed ethnic background) of childhood B-precursor ALL and compared genotype data with those of 1,417 HapMap controls. To account for the ethnic diversity of the study population, structured association by genetically matching cases and controls using identity-by-state similarity was used. Case-control association analyses were performed using Cochran-Mantel-Haenszel tests, adjusted for the population substructure. RESULTS: Common variations rs6966 (3' UTR of PPP1R13L, chr 19q13.32, P = 4.55 × 10(-9)) and rs414580 (intron 2 of MSR1, chr 8p22, P = 6.09 × 10(-8)) were significantly associated with ALL. These SNPs remained significant after adjustment for multiple testing. The SNP rs6966 tags a haplotype block which includes SNPs in PPP1R13L and ERCC2 genes, which are related to DNA repair and cell survival. rs6966 and rs414580 conferred allelic odds ratios of 3.74 (95% confidence interval [CI] 2.31-6.04) and 3.93 (95% CI 2.31-6.69), respectively. CONCLUSIONS: These findings reveal two independent novel susceptibility loci for childhood ALL.

Association of the APOE gene variants with depression in type 2 diabetes.

Background: The risk of depression among patients with diabetes is higher than the general population. The exact mechanisms linking these two diseases are mostly unknown. Energy metabolism disorders seem to be a shared pathway. One of the key genes playing important roles in energy metabolism-related pathways is the APOE gene. We aimed to investigate the association of the APOE gene variants with depression among Iranian patients with type 2 diabetes (T2DM). Methods: Three APOE gene alleles and genotypes frequencies (E2, E3, E4) were determined in 244 patients with T2DM (114 with depression and 130 without depression) using the high-resolution melting (HRM) method on the genomic DNA extracted from the patient's peripheral blood. Results: Apoe4 allele frequency was significantly higher in T2DM patients without depression compared with those with depression (11.9 vs. 2.2%, p-value < 0.0001 and p-value = 0.001, respectively). Conversely, the wild allele apoe3 frequency was significantly higher in T2DM patients with depression (86% vs., 69%, p-value < 0.0001). Apoe4 carrier status was associated with decreased risk of depression in patients with T2DM [OR: 0.19 (0.07-0.53)]. Conclusion: Our results showed that the apoe4 allele and apoe4 carrier status significantly reduced the risk of depression among patients with T2DM. Further studies are needed to unravel the complex role of the APOE gene in depression among patients with diabetes.

The need to shift pharmacogenetic research from candidate gene to genome-wide association studies.

The primary research approach in pharmacogenetics has been candidate gene association studies (CGAS), but pharmacogenomic genome-wide association studies (GWAS) are becoming more common. We are now at a critical juncture when the results of those two research approaches, CGAS and GWAS, can be compared in pharmacogenetics. We analyzed publicly available databases of pharmacogenetic CGAS and GWAS (i.e., the Pharmacogenomics Knowledgebase [PharmGKB®] and the NHGRI-EBI GWAS catalog) and the vast majority of variants (98%) and genes (94%) discovered in pharmacogenomic GWAS were novel (i.e., not previously studied CGAS). Therefore, pharmacogenetic researchers are not selecting the right candidate genes in the vast majority of CGAS, highlighting a need to shift pharmacogenetic research efforts from CGAS to GWAS.

Body site-specific genetic effects influence naevus count distribution in women.

Body site is highly relevant for melanoma: it affects prognosis and varies according to the patient's sex. The distribution of naevi, a major risk factor for melanoma, at different body sites also varies according to sex in childhood. Using naevus counts at different body sites in 492 unrelated adults from both sexes, we observed that women have an increased number of naevi on the lower limbs compared to men (p = 8.5 × 10-5 ), showing that a high naevus count on this site persists from childhood throughout life. Then, using data from 3,232 twins, we observed, in women, the lowest naevus count heritability on the trunk (26%), and the highest on the lower limbs (69%). Finally, we showed that, in 2,864 women, six genomic loci previously associated with both naevus count and melanoma risk (IRF4, DOCK8, MTAP, 9q31.2, KITLG and PLA2G6) have an effect on naevus count that is body site-specific, but whose effect sizes are predominantly stronger on the lower limbs. Sex-specific genetic influence on naevus count at different sites may explain differences in site-specific melanoma incidence as well as prognosis between sexes.

Lack of Association Between Genetic Variation in 9 Innate Immunity Genes and Baseline CRP Levels.

It is well-known that baseline levels of C-reactive protein (CRP) are an independent cardiovascular risk factor. We hypothesized that genetic variation with significant influence on CRP levels might be found in genes of the innate immunity system. We performed a candidate gene association study examining common single nucleotide polymorphisms in 9 innate immunity genes (CARD15, IRAK1, IRAK4, LBP, LY86, MEFV, TLR2, TLR4 and NFKB1) in relation to CRP levels. Seven hundred and seventeen subjects from the Women's Health Study population were studied: 359 and 358 samples with extremely low (<0.2 mg/liter) and high (>5 mg/liter) CRP levels, respectively. SNPs were identified from publicly available resequencing data, using a minor allele frequency threshold of >5% and a linkage disequilibrium (LD)-based strategy (r2 > 0.8) to select 63 LD-independent markers. One non-synonymous SNP in TLR4 and two non-synonymous SNPs in CARD15, previously associated with atherosclerosis and Crohn's disease, respectively, were also studied. Univariate, haplotype and gene-gene interaction analyses all indicated no significant association with CRP levels. Although this work excludes a significant association of common SNPs in these nine genes with CRP levels, it is possible that rarer alleles in these genes, or variation in other innate immunity genes, could be associated with variation in CRP.

Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort.

BACKGROUND: The occurrence of familial forms of sarcoidosis (OMIM 181100) suggests a genetic predisposition. The involvement of butyrophilin-like 2 (BTNL2) gene (rs2076530 variant) has to be investigated. RESULTS: The study performed independent analyses of BTNL2 polymorphism, clinical phenotypes, and outcomes in familial vs. sporadic presentations in 256 sporadic and 207 familial cases from 140 families. The logistic multivariate model showed that a young age at diagnosis and the combination of lung and skin involvement at diagnosis may distinguish sporadic from familial sarcoidosis (p = 0.016 and p = 0.041). We observed also that Sarcoid Clinical Activity Classification (SCAC) profiles were significantly different between familial and sporadic cases (p = 0.0497). Variant rs2076530 was more frequent in patients than in controls (OR = 2.02; 95% CI: [1.32-3.09]) but showed no difference between sporadic and familial cases and no difference according to the clinical phenotype or the outcome. CONCLUSION: Despite a significant difference in BTNL2 polymorphism between sarcoid patients and controls, there was no such difference between familial and sporadic sarcoidosis cases and no correlation between BTNL2 polymorphism and disease severity or outcome. Thus, BTNL2 difference cannot be considered as a key marker for disease classification or patient management.

Personalized management of asthma exacerbations: lessons from genetic studies.

INTRODUCTION: The genetics of severe asthma and asthma exacerbations are distinct from milder forms of asthma. Gene-environmental interactions contribute to the complexity and heterogeneity of severe asthma and asthma exacerbations, and pharmacogenomic studies have also identified genes that affect susceptibility to asthma exacerbations. AREAS COVERED: Studies on the genetics, gene-environment interactions, and pharmacogenomics of asthma exacerbations are reviewed. Multiple individual genetic variants have been identified to be associated with asthma exacerbations but each genetic polymorphism explains only a fraction of the disease and by itself is not able to translate into clinical practice. Research is shifting from candidate gene studies and genome wide association studies towards more integrative approaches to translate genetic findings into clinical diagnostic and therapeutic tools. EXPERT COMMENTARY: Integrative approaches combining polygenic or genomic data with multi-omics technologies have the potential to discover new biologic mechanisms and biomarkers for severe asthma and asthma exacerbations. Greater understanding of genomics and underlying biologic pathways will also lead to improved prevention and treatment, lowering costs, morbidity, and mortality. The utilization of genomic testing and personalized medicine may revolutionize asthma management, in particular for patients with severe, refractory asthma.

Association of Functional Variants of Phase I and II Genes with Chronic Obstructive Pulmonary Disease in a Serbian Population.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex disorder characterized by increased oxidative stress. Functional genetic variants of phase I and II genes are implicated in oxidants-antioxidants imbalance and may be involved in COPD development. In this study, we aimed to investigate the role of cytochrome P450 (CYP), glutathione S-transferase (GST) and microsomal epoxide hydrolase (mEH) functional variants in the pathogenesis of COPD in a Serbian population. METHODS: The genotypes of 122 COPD patients and 100 controls with normal lung function were determined for CYP1A1 *1A/*2A, CYP2E1 *1A/*5B, GSTM1 null, GSTT1 null GSTP1 Ile105Val, mEH Tyr113His and mEH His139Arg gene variants. RESULTS: Results obtained showed that GSTM1 null variant was significantly more represented in COPD patients than in controls (61.5% vs. 47.0%; OR=1.80; p=0.042). Also, a significant difference was observed for combinations of GSTM1 null and GSTP1 105Val/(Val) (38.5% vs. 24.0%; OR=1.98; p=0.029), as well as for CYP1A1 *1A/*2A, GSTM1 null and mEH 113His/(His) genotypes (7.4% vs. 1.0%; OR=7.88; p=0.025). CONCLUSIONS: These are the first data concerning the analysis of the variants of phase I and II genes in the pathogenesis of COPD in a Serbian population. Results obtained in this study open up the possibility for thorough analyses of the role of genetic factors in COPD on larger cohorts. Also, they implicate the importance of previously described genetic associations with COPD in our population, as well as reveal a new one, not reported so far.

A candidate gene association study further corroborates involvement of contactin genes in autism.

Although autism spectrum disorder (ASD) shows a high degree of heritability, only a few mutated genes and mostly de novo copy number variations (CNVs) with a high phenotypic impact have as yet been identified. In families with multiple ASD patients, transmitted CNVs often do not appear to cosegregate with disease. Therefore, also transmitted single nucleotide variants which escape detection if genetic analyses were limited to CNVs may contribute to disease risk. In several studies of ASD patients, CNVs covering at least one gene of the contactin gene family were found. To determine whether there is evidence for a contribution of transmitted variants in contactin genes, a cohort of 67 ASD patients and a population-based reference of 117 healthy individuals, who were not related to the ASD families, were compared. In total, 1,648 SNPs, spanning 12.1 Mb of genomic DNA, were examined. After Bonferroni correction for multiple testing, the strongest signal was found for a SNP located within the CNTN5 gene (rs6590473 [G], p = 4.09 × 10(-7); OR = 3.117; 95% CI = 1.603-6.151). In the ASD cohort, a combination of risk alleles of SNPs in CNTN6 (rs9878022 [A]; OR = 3.749) and in CNTNAP2 (rs7804520 [G]; OR = 2.437) was found more frequently than would be expected under random segregation, albeit this association was not statistically significant. The latter finding is consistent with a polygenic disease model in which multiple mutagenic mechanisms, operating concomitantly, elicit the ASD phenotype. Altogether, this study corroborates the possible involvement of contactins in ASD, which has been indicated by earlier studies of CNVs.

Genomics of elite sporting performance: what little we know and necessary advances.

Numerous reports of genetic associations with performance- and injury-related phenotypes have been published over the past three decades; these studies have employed primarily the candidate gene approach to identify genes that associate with elite performance or with variation in performance-and/or injury-related traits. Although generally with small effect sizes and heavily prone to type I statistic error, the number of candidate genetic variants that can potentially explain elite athletic status, injury predisposition, or indeed response to training will be much higher than that examined by numerous biotechnology companies. Priority should therefore be given to applying whole genome technology to sufficiently large study cohorts of world-class athletes with adequately measured phenotypes where it is possible to increase statistical power. Some of the elite athlete cohorts described in the literature might suffice, and collectively, these cohorts could be used for replication purposes. Genome-wide association studies are ongoing in some of these cohorts (i.e., Genathlete, Russian, Spanish, Japanese, United States, and Jamaican cohorts), and preliminary findings include the identification of one single nucleotide polymorphism (SNP; among more than a million SNPs analyzed) that associates with sprint performance in Japanese, American (i.e., African American), and Jamaican cohorts with a combined effect size of ~2.6 (P-value <5×10(-7)) and good concordance with endurance performance between select cohorts. Further replications of these signals in independent cohorts will be required, and any replicated SNPs will be taken forward for fine-mapping/targeted resequencing and functional studies to uncover the underlying biological mechanisms. Only after this lengthy and costly process will the true potential of genetic testing in sport be determined.

Polymorphism of the serotonin transporter gene (5-HTTLPR) in major depressive disorder patients in Malaysia.

INTRODUCTION: The serotonin transporter promoter (5-HTTLPR) is a potential susceptibility locus in the pathogenesis of major depressive disorder. However, data from Malaysia is lacking. The present study aimed to determine the association between the homozygous short variant of the serotonin transporter promoter gene (5-HTTLPR) with major depressive disorder. METHODS: This is a candidate gene case-control association study. The sample consists of 55 major depressive disorder probands and 66 controls. They were Malaysian descents and were unrelated. The Axis I diagnosis was determined using Mini International Neuropsychiatric Interview (M.I.N.I.). The control group comprised healthy volunteers without personal psychiatric history and family history of mood disorders. Participants' blood was sent to the Institute Medical Research for genotyping. RESULTS: The present study failed to detect an association between 5-HTTLPR ss genotype with major depressive disorder (χ(2) = 3.67, d.f. = 1, P = 0.055, odds ratio 0.25, 95% confidence interval = 0.07-1.94). Sub-analysis revealed that the frequency of l allele in healthy controls was higher (78.0%) than that of Caucasian and East Asian population. However, in view of the small sample size this study may be prone to type II error (and type I error). DISCUSSION: This preliminary study suggests that the homozygous short variant of the 5-HTTLPR did not appear to be a risk factor for increasing susceptibility to major depressive disorder.

Cost-effective prediction of gender-labeling errors and estimation of gender-labeling error rates in candidate-gene association studies.

We describe a statistical approach to predict gender-labeling errors in candidate-gene association studies, when Y-chromosome markers have not been included in the genotyping set. The approach adds value to methods that consider only the heterozygosity of X-chromosome SNPs, by incorporating available information about the intensity of X-chromosome SNPs in candidate genes relative to autosomal SNPs from the same individual. To our knowledge, no published methods formalize a framework in which heterozygosity and relative intensity are simultaneously taken into account. Our method offers the advantage that, in the genotyping set, no additional space is required beyond that already assigned to X-chromosome SNPs in the candidate genes. We also show how the predictions can be used in a two-phase sampling design to estimate the gender-labeling error rates for an entire study, at a fraction of the cost of a conventional design.