Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance.

BACKGROUND: Dysfunction in inwardly rectifying potassium channel Kir4.1 has been implicated in SeSAME syndrome, an autosomal-recessive (AR), rare, multi-systemic disorder. However, not all neurological, intellectual disability, and comorbid phenotypes in SeSAME syndrome can be mechanistically linked solely to Kir4.1 dysfunction. METHODS: We therefore performed whole-exome sequencing and identified additional genetic risk-elements that might exert causative effects either alone or in concert with Kir4.1 in a family diagnosed with SeSAME syndrome. RESULTS: Two variant prioritization pipelines based on AR inheritance and runs of homozygosity (ROH), identified two novel homozygous variants in KCNJ10 and PI4KB and five rare homozygous variants in PVRL4, RORC, FLG2, FCRL1, NIT1 and one common homozygous variant in HSPA6 segregating in all four patients. The novel mutation in KCNJ10 resides in the cytoplasmic domain of Kir4.1, a seat of phosphatidylinositol bisphosphate (PIP2) binding. The mutation altered the subcellular localization and stability of Kir4.1 in patient-specific lymphoblastoid cells (LCLs) compared to parental controls. Barium-sensitive endogenous K+ currents in patient-specific LCLs using whole-cell patch-clamp electrophysiology revealed membrane depolarization and defects in inward K+ ion conductance across the membrane, thereby suggesting a loss-of-function effect of KCNJ10 variant. CONCLUSION: Altogether, our findings implicate the role of new genes in SeSAME syndrome without electrolyte imbalance and thereby speculate the regulation of Kir4.1 channel activity by PIP2 and integrin-mediated adhesion signaling mechanisms.

A linkage and exome study implicates rare variants of KANK4 and CAP2 in bipolar disorder in a multiplex family.

OBJECTIVES: Bipolar disorder (BD) is a neuropsychiatric disorder with a complex pattern of inheritance. Although many genetic studies have been conducted on BD, its genetic correlates remain uncertain. This study was aimed at  identifying the genetic underpinnings of the disorder in an Indian family, which has been under comprehensive clinical evaluation and follow-up for over 12 years. METHODS: We analysed a four-generation family with several of its members diagnosed for BD employing a combination of genetic linkage and exome analysis. RESULTS: We obtained suggestive LOD score for a chromosome 1 and a chromosome 6 marker (D1S410; LOD = 3.01, Ó¨ = 0; and D6S289; LOD = 1.58, Ó¨ = 0). Manual haplotyping of the regions encompassing these two markers helped delimit a critical genomic interval of 32.44 Mb (D1S2700-D1S435; chromosome 1p31.1-13.2) and another of 10.34 Mb (D6S470-D6S422; chromosome 6p22.3-22.2). We examined the exomic sequences corresponding to these two intervals and found rare variants, NM_181712.4: c.2461G>T (p.Asp821Tyr) in KANK4 at 1p31.1-13.2; and NM_006366:c.-93G>A, in the 5' UTR of CAP2 at 6p22.3-22.2. CONCLUSIONS: Our studysuggests involvement of KANK4 or CAP2 or both in BD in this family. Further analysis of these two genes in BD patients and functional evaluation of the allelic variants identified are suggested.

Adverse childhood experiences in families with multiple members diagnosed to have psychiatric illnesses.

OBJECTIVE: Adverse childhood experiences are linked to the development of a number of psychiatric illnesses in adulthood. Our study examined the pattern of adverse childhood experiences and their relation to the age of onset of major psychiatric conditions in individuals from families that had ⩾2 first-degree relatives with major psychiatric conditions (multiplex families), identified as part of an ongoing longitudinal study. METHODS: Our sample consisted of 509 individuals from 215 families. Of these, 268 were affected, i.e., diagnosed with bipolar disorder (n = 61), obsessive-compulsive disorder (n = 58), schizophrenia (n = 52), substance dependence (n = 59) or co-occurring diagnoses (n = 38), while 241 were at-risk first-degree relatives who were either unaffected (n = 210) or had other depressive or anxiety disorders (n = 31). All individuals were evaluated using the Adverse Childhood Experiences - International Questionnaire and total adverse childhood experiences exposure and severity scores were calculated. RESULTS: It was seen that affected males, as a group, had the greatest adverse childhood experiences exposure and severity scores in our sample. A Cox mixed effects model fit by gender revealed that a higher total adverse childhood experiences severity score was associated with significantly increased risk for an earlier age of onset of psychiatric diagnoses in males. A similar model that evaluated the interaction of diagnosis revealed an earlier age of onset in obsessive-compulsive disorder and substance dependence, but not in schizophrenia and bipolar disorder. CONCLUSION: Our study indicates that adverse childhood experiences were associated with an earlier onset of major psychiatric conditions in men and individuals diagnosed with obsessive-compulsive disorder and substance dependence. Ongoing longitudinal assessments in first-degree relatives from these families are expected to identify mechanisms underlying this relationship.

Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes.

AIM: Severe mental illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome-wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with next-generation sequencing may add to the understanding of the genetic architecture of SMI. METHODS: We analyzed 32 ill subjects from eight multiplex families and 33 healthy individuals using whole-exome sequencing. Prioritized variants were selected by a three-step filtering process, which included: deleteriousness by five in silico algorithms; sharing within families by affected individuals; rarity in South Asian sample estimated using the Exome Aggregation Consortium data; and complete absence of these variants in control individuals from the same gene pool. RESULTS: We identified 42 rare, non-synonymous deleterious variants (~5 per pedigree) in this study. None of the variants were shared across families, indicating a 'private' mutational profile. Twenty (47.6%) of the variant harboring genes were previously reported to contribute to the risk of diverse neuropsychiatric syndromes, nine (21.4%) of which were of Mendelian inheritance. These included genes carrying novel deleterious variants, such as the GRM1 gene implicated in spinocerebellar ataxia 44 and the NIPBL gene implicated in Cornelia de Lange syndrome. CONCLUSION: Next-generation sequencing approaches in family-based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The findings of the study suggest a potential phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of SMI.

Discovery biology of neuropsychiatric syndromes (DBNS): a center for integrating clinical medicine and basic science.

BACKGROUND: There is emerging evidence that there are shared genetic, environmental and developmental risk factors in psychiatry, that cut across traditional diagnostic boundaries. With this background, the Discovery biology of neuropsychiatric syndromes (DBNS) proposes to recruit patients from five different syndromes (schizophrenia, bipolar disorder, obsessive compulsive disorder, Alzheimer's dementia and substance use disorders), identify those with multiple affected relatives, and invite these families to participate in this study. The families will be assessed: 1) To compare neuro-endophenotype measures between patients, first degree relatives (FDR) and healthy controls., 2) To identify cellular phenotypes which differentiate the groups., 3) To examine the longitudinal course of neuro-endophenotype measures., 4) To identify measures which correlate with outcome, and 5) To create a unified digital database and biorepository. METHODS: The identification of the index participants will occur at well-established specialty clinics. The selected individuals will have a strong family history (with at least another affected FDR) of mental illness. We will also recruit healthy controls without family history of such illness. All recruited individuals (N = 4500) will undergo brief clinical assessments and a blood sample will be drawn for isolation of DNA and peripheral blood mononuclear cells (PBMCs). From among this set, a subset of 1500 individuals (300 families and 300 controls) will be assessed on several additional assessments [detailed clinical assessments, endophenotype measures (neuroimaging- structural and functional, neuropsychology, psychophysics-electroencephalography, functional near infrared spectroscopy, eye movement tracking)], with the intention of conducting repeated measurements every alternate year. PBMCs from this set will be used to generate lymphoblastoid cell lines, and a subset of these would be converted to induced pluripotent stem cell lines and also undergo whole exome sequencing. DISCUSSION: We hope to identify unique and overlapping brain endophenotypes for major psychiatric syndromes. In a proportion of subjects, we expect these neuro-endophenotypes to progress over time and to predict treatment outcome. Similarly, cellular assays could differentiate cell lines derived from such groups. The repository of biomaterials as well as digital datasets of clinical parameters, will serve as a valuable resource for the broader scientific community who wish to address research questions in the area.

Bipolar disorder comorbidity in patients with a primary diagnosis of OCD.

OBJECTIVE: Bipolar disorder (BD) is considered to be a common comorbid condition in subjects with obsessive-compulsive disorder (OCD), but there is limited literature on the prevalence of BD and its clinical correlates in those with a primary diagnosis of OCD. METHODS: We studied the prevalence of BD in a sample of consecutively registered outpatients attending a specialty OCD clinic in India over a period of 13 months. One hundred and seventy-one patients with a primary diagnosis of OCD were assessed systematically using structured and semi-structured instruments. RESULTS: The prevalence of lifetime BD in OCD was 4%. The OCD + BD group had an episodic course of OCD and higher rate of lifetime suicide attempts. CONCLUSIONS: BD may not be as highly prevalent in OCD as reported in literature. Those with OCD seem to have only a marginally higher risk for developing BD than the general population. A diagnosis of BD seems to have a pathoplastic effect on the course of OCD. Patients with OCD-BD comorbidity have to be specifically assessed for suicide risk.

Comparison of clinical characteristics of familial and sporadic obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a heterogeneous condition with evidence of familiality in a considerable proportion of patients. A classification into familial and sporadic forms has been proposed to explain the heterogeneity. The current study aims to compare the demographic, clinical and comorbidity patterns of patients with and without a family history of OCD in first-degree relatives. METHOD: 802 consecutive patients who consulted a specialty OCD Clinic at a tertiary care psychiatric hospital in India were evaluated with the Mini-International Neuropsychiatric Interview, the Yale-Brown Obsessive-Compulsive Scale, and the Clinical Global Impression Scale. Family history was assessed by interviewing patients and at least one first-degree relative. RESULTS: Family history of OCD was seen in 152 patients (19%). Family history was associated with juvenile onset (Χ(2)=19.472, p<0.001), obsessions of contamination (Χ(2)=6.658, p=0.01), hoarding (Χ(2)=4.062, p=0.032), need for symmetry (Χ(2)=3.95, p=0.047), washing compulsion (Χ(2)=7.923, p=0.005), ordering compulsions (Χ(2)=6.808, p=0.009), repeating compulsions (Χ(2)=4.950, p=0.026) and compulsions by proxy (Χ(2)=7.963, p=0.005). Family history was also associated with greater severity of OCD (t=-2.31, p=0.022) and compulsions (t=-3.09, p=0.002) and longer duration of illness at presentation (t=-2.93, p=0.004). CONCLUSION: Our findings suggest that familial OCD may have distinctive clinical features. Studying familial forms of OCD may offer unique insight in to understanding the genetic basis of OCD.

A cross ancestry genetic study of psychiatric disorders from India.

Genome-wide association studies across diverse populations may help validate and confirm genetic contributions to risk of disease. We estimated the extent of population stratification as well as the predictive accuracy of polygenic scores (PGS) derived from European samples to a data set from India. We analysed 2685 samples from two data sets, a population neurodevelopmental study (cVEDA) and a hospital-based sample of bipolar affective disorder (BD) and obsessive-compulsive disorder (OCD). Genotyping was conducted using Illumina's Global Screening Array. Population structure was examined with principal component analysis (PCA), uniform manifold approximation and projection (UMAP), support vector machine (SVM) ancestry predictions, and admixture analysis. PGS were calculated from the largest available European discovery GWAS summary statistics for BD, OCD, and externalizing traits using two Bayesian methods that incorporate local linkage disequilibrium structures (PGS-CS-auto) and functional genomic annotations (SBayesRC). Our analyses reveal global and continental PCA overlap with other South Asian populations. Admixture analysis revealed a north-south genetic axis within India (FST 1.6%). The UMAP partially reconstructed the contours of the Indian subcontinent. The Bayesian PGS analyses indicates moderate-to-high predictive power for BD. This was despite the cross-ancestry bias of the discovery GWAS dataset, with the currently available data. However, accuracy for OCD and externalizing traits was much lower. The predictive accuracy was perhaps influenced by the sample size of the discovery GWAS and phenotypic heterogeneity across the syndromes and traits studied. Our study results highlight the accuracy and generalizability of newer PGS models across ancestries. Further research, across diverse populations, would help understand causal mechanisms that contribute to psychiatric syndromes and traits.

Altered neuroepithelial morphogenesis and migration defects in iPSC-derived cerebral organoids and 2D neural stem cells in familial bipolar disorder.

Bipolar disorder (BD) is a severe mental illness that can result from neurodevelopmental aberrations, particularly in familial BD, which may include causative genetic variants. In the present study, we derived cortical organoids from BD patients and healthy (control) individuals from a clinically dense family in the Indian population. Our data reveal that the patient organoids show neurodevelopmental anomalies, including organisational, proliferation and migration defects. The BD organoids show a reduction in both the number of neuroepithelial buds/cortical rosettes and the ventricular zone size. Additionally, patient organoids show a lower number of SOX2-positive and EdU-positive cycling progenitors, suggesting a progenitor proliferation defect. Further, the patient neurons show abnormal positioning in the ventricular/intermediate zone of the neuroepithelial bud. Transcriptomic analysis of control and patient organoids supports our cellular topology data and reveals dysregulation of genes crucial for progenitor proliferation and neuronal migration. Lastly, time-lapse imaging of neural stem cells in 2D in vitro cultures reveals abnormal cellular migration in BD samples. Overall, our study pinpoints a cellular and molecular deficit in BD patient-derived organoids and neural stem cell cultures.

Selected rapporteur summaries from the XX World Congress of Psychiatric Genetics, Hamburg, Germany, October 14-18, 2012.

The XXth World Congress of Psychiatric Genetics (WCPG), sponsored by The International Society of Psychiatric Genetics (ISPG) took place in Hamburg, Germany on October 14-18, 2012. Approximately 600 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned sessions as rapporteurs. This manuscript represents topics covered in most, but not all, oral presentations during the conference, and some of the major notable new findings reported at this 2012 WCPG.

Generation of feeder-independent transgene-free iPSC lines from a young-onset Parkinson's disease (YOPD) patient with a homozygous PLA2G6: c.2222G>A (p. Arg741Gln) mutation (NCBSi003-A) and unaffected heterozygous parent (NCBSi004-A).

Phospholipase A2 group 6 (PLA2G6, iPLA2ß or PARK14) gene encodes a calcium-independent group 6 phospholipase A2 enzyme and is associated with young-onset autosomal recessive Parkinson's disease (PD). We generated human induced pluripotent stem cell (iPSC) lines from a patient with young-onset PD carrying a homozygous PLA2G6: c.2222G>A (p. Arg741Gln) mutation (NCBSi003-A) and unaffected heterozygous parent (NCBSi004-A). These iPSC lines will be used for investigating the key molecular signatures of young-onset PD (YOPD), and to understand the predictive phenotypes of the disease.

A study of genetic variants, genetic risk score and DNA methylation of PNPLA3 and TM6SF2 in alcohol liver cirrhosis.

BACKGROUND: Genetic and epigenetic factors are associated with the development of alcohol-associated liver disease (AALD). The single nucleotide polymorphisms (SNPs), rs738409 in Patatin-like phospholipase domain-containing protein (PNPLA3) and rs58542926 in Transmembrane 6 Superfamily Member 2 (TM6SF2) are strongly associated with AALD in different global populations, Hence, we analyzed the genetic risk score for these variants and deoxyribonucleic acid (DNA) methylation levels of the PNPLA3 and TM6SF2 genes among cases (alcohol liver cirrhosis) and controls (heavy drinkers without cirrhosis). METHOD: We studied patients with alcohol use disorder (AUD) with cirrhosis (AUD-C + ve, n = 136) and without cirrhosis (AUD-C-ve, n = 107) drawn from the clinical services of St. John's Medical College Hospital (SJMCH) (Gastroenterology and Psychiatry) and Centre for Addiction Medicine (CAM), National Institute of Mental Health and Neurosciences, (NIMHANS). Genotype data was generated for rs738409 (PNPLA3) and rs58542926 (TM6SF2) and used to calculate unweighted genetic risk score (uGRS) and weighted genetic risk scores (wGRS). DNA methylation levels were estimated by pyrosequencing at PNPLA3 and TM6SF2 loci. RESULTS: Overall we observed a significantly higher genetic risk score (weighted genetic risk score, wGRS) in individuals with alcohol use disorder compared to control population (p = < 0.01). Further, uGRS and wGRS were associated with the diagnosis of cirrhosis, even after correcting for age of onset, quantity and frequency of drinking. We also found hypomethylation at CpG2 of TM6SF2 gene in AUD-C + ve compared to AUD-C-ve (P = 0.02). CONCLUSION: We found that a genetic risk score based on SNPs in the PNPLA3 and TM6SF2 genes was significantly associated with cirrhosis in patients with AUD, suggesting a potential utility in identifying patients at risk and providing pre-emptive interventions. These may include interventions that aim to alter DNA methylation, which may be one of the mechanisms through which elevated genetic risk may influence the development of cirrhosis.

Hypomethylation of Long Interspersed Nucleotide Elements and Aldehyde Dehydrogenase in Patients of Alcohol Use Disorder with Cirrhosis.

Alcohol use disorder (AUD) and cirrhosis are key outcomes of excessive alcohol use, and a genetic influence in these outcomes is increasingly recognized. While 80-90% of heavy alcohol users show evidence of fatty liver, only 10-20% progress to cirrhosis. There is currently no clear understanding of the causes of this difference in progression. The aim of this study is to evaluate genetics and epigenetics at the aldehyde dehydrogenase (ALDH2) locus in patients with AUD and liver complications. Study participants were inpatients from the clinical services of Gastroenterology and Psychiatry at St. John's Medical College Hospital (SJMCH) and the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. Men diagnosed as having AUD with cirrhosis (AUDC+ve, N = 136) and AUD without cirrhosis (AUDC-ve, N = 107) were assessed. FibroScan/sonographic evidence was used to rule out fibrosis in the AUDC-ve group. Genomic DNA was used for genotyping at the ALDH2 (rs2238151) locus. A subset of 89 samples was used for DNA methylation (AUDC+ve, N = 44; and AUDC-ve, N = 45) analysis at long interspersed nucleotide element 1 (LINE-1) and ALDH2 cytosine-phosphate-guanine (CpG) loci by pyrosequencing. ALDH2 DNA methylation was significantly lower in the AUDC+ve group compared with the AUDC-ve group (p < 0.001). Lower methylation was associated with a risk allele (T) of the ALDH2 locus (rs2238151) (p = 0.01). Global (LINE-1) DNA methylation levels were also significantly lower in the AUDC+ve group compared with the AUDC-ve group (p = 0.01). Compromised global methylation (LINE-1) and hypomethylation at the ALDH2 gene was observed in patients with cirrhosis compared with those without cirrhosis. DNA methylation could be explored as a biomarker for cirrhosis and liver complications.

Comparison of gut microbiome profile in patients with schizophrenia and healthy controls - A plausible non-invasive biomarker?

The human gut microbiome regulates brain function through the microbiome-gut-brain axis and is implicated in several neuropsychiatric disorders. However, the relationship between the gut microbiome and the pathogenesis of schizophrenia (SCZ) is poorly defined, and very few studies have examined the effect of antipsychotic treatment response. We aim to study the differences in the gut microbiota among drug-naïve (DN SCZ) and risperidone-treated SCZ patients (RISP SCZ), compared to healthy controls (HCs). We recruited a total of 60 participants, from the clinical services of a large neuropsychiatric hospital, which included DN SCZ, RISP SCZ and HCs (n = 20 each). Fecal samples were analyzed using 16s rRNA sequencing in this cross-sectional study. No significant differences were found in taxa richness (alpha diversity) but microbial composition differed between SCZ patients (both DN and RISP) and HCs (PERMANOVA, p = 0.02). Linear Discriminant Analysis Effect Size (LEfSe) and Random Forest model identified the top six genera, which significantly differed in abundance between the study groups. A specific genus-level microbial panel of Ruminococcus, UCG005, Clostridium_sensu_stricto_1 and Bifidobacterium could discriminate SCZ patients from HCs with an area under the curve (AUC) of 0.79, HCs vs DN SCZ (AUC: 0.68), HCs vs RISP SCZ (AUC: 0.93) and DN SCZ vs RISP SCZ (AUC: 0.87). Our study identified distinct microbial signatures that could aid in the differentiation of DN SCZ, RISP SCZ, and HCs. Our findings contribute to a better understanding of the role of the gut microbiome in SCZ pathophysiology and suggest potential targeted interventions.

Psychological impact of the tsunami on elderly survivors.

OBJECTIVE: The study aimed at comparing the psychiatric morbidity in geriatric versus nongeriatric (NG) adults during the initial 3 months following the December 2004 tsunami involving the Andaman and Nicobar Islands, India. METHODS: This observational study was undertaken during the relief operation of tsunami. There were 12,784 survivors sheltered across 74 relief camps with 4,684 displaced survivors in Port Blair, and 8,100 nondisplaced survivors in Car Nicobar Island. All persons who accessed mental health assistance within the camps constituted the study sample. Diagnoses were made by qualified psychiatrists using the International Classification of Diseases, Tenth Revision. There were 438 adult patients, of which 75 (17%) were geriatric (60 years or older) and 363 (83%) were NG (aged 19-59 years). RESULTS: The geriatric sample had greater levels of adjustment disorder than NG group. The two groups differed in terms of displacement as the elderly preferred to stay in their own locality. A comparison between displaced geriatric and NG groups showed that major depression was less common in the geriatric sample. However, in the nondisplaced group, geriatric subgroup showed a higher incidence of posttraumatic stress disorder. Within the geriatric sample, there were higher levels of adjustment disorder in the nondisplaced group whereas the displaced group suffered more depressive episodes and unspecified anxiety disorders. CONCLUSION: Greater levels of adjustment disorder in geriatric group may indicate grief reaction and survivor guilt, especially in nondisplaced group. In addition, lower occurrences of depressive episodes in nondisplaced geriatric sample may indicate that the elderly need to be rehabilitated in their own habitats after major disasters.

White matter abnormalities in children and adolescents with obsessive-compulsive disorder: a diffusion tensor imaging study.

BACKGROUND: There is paucity of data on white matter (WM) abnormalities in juvenile obsessive-compulsive disorder (OCD). This study aimed to identify WM microstructure changes in juvenile OCD. METHODS: Fifteen children and adolescents with OCD and 15 matched healthy controls underwent diffusion tensor imaging using a 3 Tesla (Achieva, Best, The Netherlands) magnetic resonance imaging scanner. Voxelwise analyses were conducted on data processed through tract-based spatial statistics (TBSS). RESULTS: Patients significantly differed from controls in axial as well as radial diffusivities, but not in fractional anisotropy. Patients demonstrated significantly increased axial diffusivity in corpus callosum (genu, body, and splenium), right and left superior longitudinal fasciculi, left inferior longitudinal fasciculus, right and left cingulum, bilateral anterior thalamic radiations, bilateral anterior limb of internal capsule, left posterior limb of the internal capsule, and middle cerebellar peduncle. In addition, significantly increased radial diffusivity was seen in patients in genu of the corpus, right and left superior longitudinal fasciculi, left inferior longitudinal fasciculus, right and left uncinate fasciculi, bilateral anterior thalamic radiation, bilateral inferior fronto-occipital fasciculus, left posterior limb of internal capsule, right superior cerebellar peduncle, middle cerebellar peduncle, and right inferior cerebellar peduncle. CONCLUSIONS: Our findings suggest involvement of multiple WM tracts in juvenile OCD. In addition to the widely proposed hypothesis of orbitofrontal-striato-thalamo-cortical circuitry deficits in the development of OCD, our findings suggest involvement of additional brain regions, possibly parietal cortex, lateral prefrontal cortex, and limbic system. The widespread differences in WM among cases and controls also points to the possibility of underlying myelination changes.

Impact of depressive and anxiety disorder comorbidity on the clinical expression of obsessive-compulsive disorder.

BACKGROUND: The identification of distinct subtypes based on comorbidity offers potential utility in understanding variations in the clinical expression of obsessive-compulsive disorder (OCD). Hence, we examined the hypothesis whether patients with OCD with major depressive disorder (MDD) or anxiety disorder comorbidity would differ from those without in terms of phenomenology. METHODS: A total of 545 consecutive patients who consulted a specialty OCD clinic during the period 2004 to 2009 at a psychiatric hospital in India formed the sample. They were evaluated with the Yale-Brown Obsessive-Compulsive Scale (YBOCS), the Mini International Neuropsychiatric Interview, and the Clinical Global Impression scale. RESULTS: Among 545 patients, 165 (30%) had current MDD, and 114 (21%) had current anxiety disorder comorbidity. Patients with OCD with MDD were mostly women who had a greater severity of OCD symptoms, more of obsessions (especially religious), greater occurrence of miscellaneous compulsions (need to confess or need to touch), higher suicidal risk, and past suicidal attempts. Patients with OCD with anxiety disorder had an earlier onset of illness that was associated with prior life events, less of compulsions, more of aggressive and hoarding obsessions, pathologic doubts, checking, and cognitive compulsions. CONCLUSIONS: Obsessive-compulsive disorder, when comorbid with MDD, is more severe and is associated with higher suicidal risk. On the other hand, anxiety disorder comorbidity seems to influence not so much the morbidity but the phenotypic expression of OCD.

Generation of a new human induced pluripotent stem cell (hiPSC) line from a South Asian Indian with a MYBPC3Δ25bp variant.

Myosin binding protein C3 (MYBPC3) is a thick filament contractile protein that interacts with myosin, titin and actin and regulates cardiac muscle contraction. Genetic variations in the MYBPC3 gene are known causal factors for cardiomyopathy and heart failure. Previously, we identified a recurrent MYBPC3 deletion (25 base pairs) among South Asians associated with cardiomyopathy and heart failure. Here, we generated an induced pluripotent stem cell (iPSC) line using peripheral blood mononuclear cells (PBMC) from an Indian harboring MYBPC3 deletion. This iPSC line displayed embryonic stem cell morphology, expressed pluripotency markers, differentiated into three germ layers and exhibited normal karyotype.

Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes.

Whole Exome Sequencing (WES) studies provide important insights into the genetic architecture of serious mental illness (SMI). Genes that are central to the shared biology of SMIs may be identified by WES in families with multiple affected individuals with diverse SMI (F-SMI). We performed WES in 220 individuals from 75 F-SMI families and 60 unrelated controls. Within pedigree prioritization employed criteria of rarity, functional consequence, and sharing by ≥ 3 affected members. Across the sample, gene and gene-set-wide case-control association analysis was performed with Sequence Kernel Association Test (SKAT). In 14/16 families with ≥ 3 sequenced affected individuals, we identified a total of 78 rare predicted deleterious variants in 78 unique genes shared by ≥ 3 members with SMI. Twenty (25%) genes were implicated in monogenic CNS syndromes in OMIM (OMIM-CNS), a fraction that is a significant overrepresentation (Fisher's Exact test OR = 2.47, p = 0.001). In gene-set SKAT, statistically significant association was noted for OMIM-CNS gene-set (SKAT-p = 0.005) but not the synaptic gene-set (SKAT-p = 0.17). In this WES study in F-SMI, we identify private, rare, protein altering variants in genes previously implicated in Mendelian neuropsychiatric syndromes; suggesting pleiotropic influences in neurodevelopment between complex and Mendelian syndromes.

Abnormalities in the migration of neural precursor cells in familial bipolar disorder.

Cellular migration is a ubiquitous feature that brings brain cells into appropriate spatial relationships over time; and it helps in the formation of a functional brain. We studied the migration patterns of induced pluripotent stem cell-derived neural precursor cells (NPCs) from individuals with familial bipolar disorder (BD) in comparison with healthy controls. The BD patients also had morphological brain abnormalities evident on magnetic resonance imaging. Time-lapse analysis of migrating cells was performed, through which we were able to identify several parameters that were abnormal in cellular migration, including the speed and directionality of NPCs. We also performed transcriptomic analysis to probe the mechanisms behind the aberrant cellular phenotype identified. Our analysis showed the downregulation of a network of genes, centering on EGF/ERBB proteins. The present findings indicate that collective, systemic dysregulation may produce the aberrant cellular phenotype, which could contribute to the functional and structural changes in the brain reported for bipolar disorder. This article has an associated First Person interview with the first author of the paper.