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.

Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes.

Evolutionary trends may underlie some aspects of the risk for common, non-communicable disorders, including psychiatric disease. We analyzed whole exome sequencing data from 80 unique individuals from India coming from families with two or more individuals with severe mental illness. We used Population Branch Statistics (PBS) to identify variants and genes under positive selection and identified 74 genes as candidates for positive selection. Of these, 20 were previously associated with Schizophrenia, Alzheimer's disease and cognitive abilities in genome wide association studies. We then checked whether any of these 74 genes were involved in common biological pathways or related to specific cellular or molecular functions. We found that immune related pathways and functions related to innate immunity such as antigen binding were over-represented. We also evaluated for the presence of Neanderthal introgressed segments in these genes and found Neanderthal introgression in a single gene out of the 74 candidate genes. However, the introgression pattern indicates the region is unlikely to be the source for selection. Our findings hint at how selection pressures in individuals from families with a history of severe mental illness may diverge from the general population. Further, it also provides insights into the genetic architecture of severe mental illness, such as schizophrenia and its link to immune factors.

Association study of BDNF Val66Met gene polymorphism with bipolar disorder and lithium treatment response in Indian population.

BACKGROUND: The association of the Val66Met (rs6265) polymorphism in the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder (BD) and response to lithium treatment has been suggested, though inconsistently. The considerable diversity of allele frequency across different populations contributes to this. There is no data from South Asia till date. Hence, we examined the association of this polymorphism in BD cases from India, and its association with lithium treatment response. METHODS: BD patients (N = 301) were recruited from the clinical services of National Institute of Mental Health and Neurosciences (NIMHANS), India. Lithium treatment response for 190 BD subjects was assessed using Alda scale by NIMH life charts. Patients with total score ⩾7 were defined as lithium responders (N = 115) and patients with score <7 were defined as lithium non-responders (N = 75). Healthy controls (N = 484) with no lifetime history of neuropsychiatric illness or a family history of mental illness were recruited as control set. Genotyping was performed by TaqMan genotyping assay. RESULTS: Genotype and allele frequency of BDNF Val66Met SNP was significantly different (χ2 = 7.78, p = 0.02) in cases compared to controls, and the Val(G) allele was more frequent (χ2 = 7.08, p = 0.008) in BD patients. However, no significant difference is noted in genotype or allele frequencies of this polymorphism between the lithium responders and non-responders. CONCLUSIONS: The Val(G) allele of BDNF Val66Met polymorphism is associated with risk of BD in this sample, but it is not related to response to lithium.

Cross-diagnostic evaluation of minor physical anomalies in psychiatric disorders.

BACKGROUND: Minor physical anomalies (MPA) are markers of impaired neurodevelopment during the prenatal stage. Assessing MPA across psychiatric disorders may help understand their shared nature. In addition, MPA in family members would indicate a shared liability and endophenotype potential. We examined familial aggregation of MPA and their role as transdiagnostic and disorder-specific markers of 5 major psychiatric/neuropsychiatric conditions (schizophrenia, bipolar disorder, substance dependence, obsessive-compulsive disorder, and Alzheimer's dementia). METHODS: Modified Waldrop's MPA scale was applied on 1321 individuals from 439 transdiagnostic multiplex families and 125 healthy population controls (HC). Stage of fetal development (morphogenetic/phenogenetic)- and anatomical location (craniofacial/peripheral)-based sub-scores were calculated. Familiality and endophenotypic potential of MPA were analyzed with serial negative binomial mixed-effect regression. Cross-diagnostic differences and the effect of family history density (FHD) of each diagnosis on MPA were assessed. Mixed-effects Cox models estimated the influence of MPA on age-at-onset of illness (AAO). RESULTS: MPA were found to be heritable in families with psychiatric disorders, with a familiality of 0.52. MPA were higher in psychotic disorders after controlling for effects of sex and intrafamilial correlation. Morphogenetic variant MPA was noted to be lower in dementia in comparison to HC. FHD of schizophrenia and bipolar disorder predicted higher, and that of dementia and substance dependence predicted lower MPA. MPA brought forward the AAO [HR:1.07 (1.03-1.11)], and this was more apparent in psychotic disorders. CONCLUSION: MPA are transmissible in families, are specifically related to the risk of developing psychoses, and predict an earlier age at onset. Neurodevelopmentally informed classification of MPA has the potential to enhance the etiopathogenic and translational understanding of psychiatric disorders.

Cell cycle abnormality is a cellular phenotype in OCD.

Abnormal indices of cell cycle regulation have been reported in multiple psychiatric disorders. Though reports specific to Obsessive Compulsive Disorder (OCD) are scant, numerous studies have highlighted partly common underlying biology in psychiatric disorders, cell cycle regulation being one such process. In this study, we therefore aimed to explore cell cycle in OCD. To the best of our knowledge, this is the first study to investigate these effects in OCD. We also evaluated the effect of in vitro fluoxetine, commonly used serotonin reuptake inhibitor (SRI) in OCD patients, on cell cycle regulation. The effects of both disease (OCD) and treatment (SRI) were assessed using lymphoblastoid cell lines (LCLs), derived from OCD patients and healthy controls, as a model system. LCLs were treated with 10µM of fluoxetine for 24 h, and the percentage of cells in each phase of the cell cycle was determined by flow cytometry. We observed a lower proportion of cells in the G2/M phase in OCD cases than controls. The findings suggest that cell cycle dysregulation could be peripheral cellular phenotype for OCD. Among cases, all of whom had been systematically characterized for SRI treatment response, LCLs from non-responders to SRI treatment had a lower proportion of cells in G2/M phase than responders.

Estimating the familial risk of psychiatric illnesses: A review of family history scores.

A history of psychiatric illnesses in family members of those diagnosed to have an illness has been of significant interest both in research and in clinical practice. Almost all of the major psychiatric illnesses have a familial component to them, perhaps influenced by genetics and a shared environment or their combination. Systematic attempts have been made to quantify these familial risks, as obtained from family history (FH) of psychiatric illnesses. The methods range from a simple dichotomous or count scores to those quantifying as weighted risks such as the Family history density (FHD) measures. This article reviews the available literature on such FH methods and discusses their advantages and limitations. Validation studies have shown that FHD measures may be preferred over dichotomous measures as indicators of familial risk. However, the FHD method has certain limitations, like mostly relying on categorical diagnosis and ignoring other familial risk factors. By critically analysing various existing density measures based on 'ideal characteristics', we suggest a modified version of FHD that would benefit psychiatric research.

Psychiatric symptoms and syndromes transcending diagnostic boundaries in Indian multiplex families: The cohort of ADBS study.

Syndromes of schizophrenia, bipolar disorder, obsessive-compulsive disorder, substance use disorders and Alzheimer's dementia are highly heritable. About 10-20% of subjects have another affected first degree relative (FDR), and thus represent a 'greater' genetic susceptibility. We screened 3583 families to identify 481 families with multiple affected members, assessed 1406 individuals in person, and collected information systematically about other relatives. Within the selected families, a third of all FDRs were affected with serious mental illness. Although similar diagnoses aggregated within families, 62% of the families also had members with other syndromes. Moreover, 15% of affected individuals met criteria for co-occurrence of two or more syndromes, across their lifetime. Using dimensional assessments, we detected a range of symptom clusters in both affected and unaffected individuals, and across diagnostic categories. Our findings suggest that in multiplex families, there is considerable heterogeneity of clinical syndromes, as well as sub-threshold symptoms. These families would help provide an opportunity for further research using both genetic analyses and biomarkers.

Lithium response in bipolar disorder correlates with improved cell viability of patient derived cell lines.

Lithium is an effective, well-established treatment for bipolar disorder (BD). However, the mechanisms of its action, and reasons for variations in clinical response, are unclear. We used neural precursor cells (NPCs) and lymphoblastoid cell lines (LCLs), from BD patients characterized for clinical response to lithium (using the "Alda scale" and "NIMH Retrospective Life chart method"), to interrogate cellular phenotypes related to both disease and clinical lithium response. NPCs from two biologically related BD patients who differed in their clinical response to lithium were compared with healthy controls. RNA-Seq and analysis, mitochondrial membrane potential (MMP), cell viability, and cell proliferation parameters were assessed, with and without in vitro lithium. These parameters were also examined in LCLs from 25 BD patients (16 lithium responders and 9 non-responders), and 12 controls. MMP was lower in both NPCs and LCLs from BD; but it was reversed with in vitro lithium only in LCLs, and this was unrelated to clinical lithium response. The higher cell proliferation observed in BD was unaffected by in vitro lithium. Cell death was greater in BD. However, LCLs from clinical lithium responders could be rescued by addition of in vitro lithium. In vitro lithium also enhanced BCL2 and GSK3B expression in these cells. Our findings indicate cellular phenotypes related to the disease (MMP, cell proliferation) in both NPCs and LCLs; and those related to clinical lithium response (cell viability, BCL2/GSK3B expression) in LCLs.

Association of SLC1A1 gene polymorphism with obsessive compulsive disorder in a sample from southern India.

The glutamate transporter gene SLC1A1 has been shown to have an association with obsessive-compulsive disorder (OCD), and serotonin reuptake inhibitor (SRI) treatment response. One polymorphism (rs3056) in SLC1A1 has been associated with altered brain volumes in OCD. We investigated the association of this polymorphism with OCD and its relationship with various clinical parameters, including age of onset, disease severity, insight, factor analyzed symptom dimensions of OCD, and SRI treatment response. Three hundred seventy seven OCD patients (DSM-IV) aged between 18 to 60 years were recruited from a specialty OCD clinic. To study the association with SRI treatment response, we analyzed full responders (≥35% reduction in the Yale Brown Obsessive Compulsive Scale [YBOCS] and the Clinical Global Impression-Improvement [CGI-I] score of 1 or 2) to any SRI (n = 187) and nonresponders (<25% reduction in the YBOCS and the CGI-I score >4) to adequate trials of at least two SRIs for a duration of 12 weeks (n = 91). Healthy controls (n = 333) were recruited and evaluated using the Mini-International Neuropsychiatric Interview-Plus (MINI-Plus). All subjects were from southern India, and were genotyped for the SLC1A1 polymorphism (rs3056). Genotype frequencies did not deviate significantly from the Hardy-Weinberg equilibrium. Case-control association analysis revealed that the "GG" genotype was significantly more frequent in OCD cases than the controls (p = .04). No association was found with the age of onset, symptom severity, insight, and symptom dimensions. No significant association was found between genotype/allele frequencies with treatment response. To conclude, although there was a significant association between the SLC1A1 rs3056 polymorphism and OCD, there were no significant associations with other clinical parameters or treatment response. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Clinical factors associated with lithium treatment response in bipolar disorder patients from India.

BACKGROUND: Bipolar Disorder (BD) is a chronic and disabling psychiatric illness with waxing and waning course. Lithium is the mainstay of treatment for Bipolar disorder (BD). There is limited literature on the clinical markers of Lithium treatment response from south Asia. METHODS: Two hundred and ten individuals with BD I and a history of at least 6 months of treatment with Lithium were recruited from the outpatient services of the National Institute of Mental Health and Neurosciences (NIMHANS) after obtaining informed consent. A diagnosis of BD I was made according to the DSM-IV criteria. The characterization of response to lithium prophylaxis was done using NIMH Retrospective Life Chart and "Retrospective Criteria of Long Term Treatment Response in Research Subjects with Bipolar Disorder" scale. RESULTS: There were 132 (62.86%) good responders and 78 (37.14%) non-responders. Good responders were noted to have less number of hospitalizations and more onset episode of depression than non-responders. Using continuous phenotype, Lithium response was inversely correlated with total number of episodes, number of episodes of mania/ depression, number of hospitalisations and presence of suicide attempt. Multivariate analysis only revealed number of episodes and hospitalization to be associated with Lithium response. CONCLUSION: Our Lithium response rates were higher than what have been reported in the few previous studies. Illness severity was the only factor associated with Lithium response. There is a need to examine this question in larger prospective samples and to focus on biological/ molecular markers of treatment response.