Molecular genetics of neuropsychiatric illness: some musings

Research into the genetic underpinnings of neuropsychiatric illness has occurred at many levels. As more information accumulates, it appears that many approaches may each offer their unique perspective. The search for low penetrance and common variants, that may mediate risk, has necessitated the formation of many international consortia, to pool resources, and achieve the large sample sizes needed to discover these variants. There has been the parallel development of statistical methods to analyse large datasets and present summary statistics which allows data comparison across studies. Even so, the results of studies on well-characterised clinical datasets of modest sizes can be enlightening and provide important clues to understanding these complex disorders. We describe the use of common variants, at multiallelic loci like TOMM40 and APOE to study dementia, weighted genetic risk scores for alcohol-induced liver cirrhosis and whole exome sequencing to identify rare variants in genes like PLA2G6 in familial psychoses and schizophrenia in our Indian population

Psychiatric morbidity and poor follow-up underlie suboptimal functional and survival outcomes in Huntington’s disease

Background: Huntington’s disease (HD), an inherited, often late-onset, neurodegenerative disorder, is considered to be a rare, orphan disease. Research into its genetic correlates and services for those affected are inadequate in most low-middle income countries, including India. The apparent ‘incurability’ often deters symptomatic and rehabilitative care, resulting in poor quality of life and sub-optimal outcomes. There are no studies assessing disease burden and outcomes from India. Methods: We attempted to evaluate individuals diagnosed to have HD at our tertiary-care center between 2013 and 2016 for clinical symptoms, functionality, mortality, follow up status through a structured interview, clinical data from medical records and UHDRS-TFC scoring. Results: Of the 144 patients, 25% were untraceable, and another 17 (11.8%) had already died. Mean age at death and duration of illness at the time of death, were 53 years and 7 years respectively, perhaps due to suicides and other comorbidities at an early age. The patients who could be contacted (n = 81) were assessed for morbidity and total functional capacity (TFC). Mean CAG repeat length and TFC score were 44.2 and 7.5 respectively. Most individuals (66%) were in TFC stage I and II and could perhaps benefit from several interventions. The TFC score correlated inversely with duration of illness (p < 0.0001). The majority were being taken care of at home, irrespective of the physical and mental disability. There was a high prevalence of psychiatric morbidity (91%) including suicidal tendency (22%). Three of the 17 who died had committed suicide, and several other families reported suicidal history in other family members. Only about half the patients (57%) maintained a regular clinical follow-up. Conclusions: This study demonstrates the poor follow-up rates, significant suicidality and other psychiatric symptoms, sub-optimal survival durations and functional outcomes highlighting the need for holistic care for the majority who appear to be amenable to interventions

Dementia and Diabetes Mellitus: Association with Apolipoprotein E4 Polymorphism from a Hospital in Southern India

Objective. To evaluate the association of Apolipoprotein E4 (ApoE4) in Alzheimer's dementia (AD) with comorbid diabetes mellitus (DM). Methods. The study included subjects with Alzheimer's dementia (AD) (n = 209), individuals with non-Alzheimer's dementia (nAD) (n = 122), individuals with parental history of AD (f/hAD) (n = 70), and control individuals who had normal cognitive functions and no parental history of dementia (NC) (n = 193). Dementia was diagnosed using International Classification of Diseases-10 revision (ICD-10) criteria. DM was assessed on the basis of self-report and/or use of antidiabetic medications. ApoE genotyping was done using sequence-specific primer polymerase chain reaction. Results. ApoE4 allele frequencies were highest among AD with comorbid DM (0.35) followed by AD without DM (0.25), nAD with DM (0.13), nAD without comorbid DM (0.12), and NC (0.08). Frequency of ApoE4 in persons with f/hAD was 0.13. The association of AD with co-morbid DM in ApoE4 carriers was more in comparison to NC with DM (OR = 5.68, P = 0.04). Conclusion. There is a significant association between AD with co-morbid DM and ApoE4 genotype

Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA):A developmental cohort study protocol

Background: Low and middle-income countries like India with a large youth population experience a different environment from that of high-income countries. The Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA), based in India, aims to examine environmental influences on genomic variations, neurodevelopmental trajectories and vulnerability to psychopathology, with a focus on externalizing disorders. Methods: cVEDA is a longitudinal cohort study, with planned missingness design for yearly follow-up. Participants have been recruited from multi-site tertiary care mental health settings, local communities, schools and colleges. 10,000 individuals between 6 and 23 years of age, of all genders, representing five geographically, ethnically, and socio-culturally distinct regions in India, and exposures to variations in early life adversity (psychosocial, nutritional, toxic exposures, slum-habitats, socio-political conflicts, urban/rural living, mental illness in the family) have been assessed using age-appropriate instruments to capture socio-demographic information, temperament, environmental exposures, parenting, psychiatric morbidity, and neuropsychological functioning. Blood/saliva and urine samples have been collected for genetic, epigenetic and toxicological (heavy metals, volatile organic compounds) studies. Structural (T1, T2, DTI) and functional (resting state fMRI) MRI brain scans have been performed on approximately 15% of the individuals. All data and biological samples are maintained in a databank and biobank, respectively. Discussion: The cVEDA has established the largest neurodevelopmental database in India, comparable to global datasets, with detailed environmental characterization. This should permit identification of environmental and genetic vulnerabilities to psychopathology within a developmental framework. Neuroimaging and neuropsychological data from this study are already yielding insights on brain growth and maturation patterns.</p

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Not AvailableOryza brachyantha, the African wild rice which is resistant to yellow stem borer (YSB), was exploited as a source for introgression of YSB resistance trait into cultivated rice (O. sativa), through development of monosomic alien addition lines (MAALs). BC2F1 backcross hybrids (O. sativa cv Savitri/O. brachyantha//O. sativa cv Savitri/// O. sativa cv Savitri) were produced employing embryo rescue, with a crossability of 0.12 %. Hybrid embryos that were collected at 10 and 12 days after pollination showed highest percentage of survival in culture with a germination percentage of 35.8 %. Cytological analysis of pollen mother cells (PMCs) of the BC2F1 hybrids revealed 15 hybrids with 2n ? 1(2n = 25) chromosome number that exhibited typical trisomic chromosomal configurations. These aneuploids were putatively designated as MAALs and characterized morphologically and cytologically. Based on their morphological similarity to primary trisomics of the cultivated rice (O. sativa), 8 MAALs viz., MAALs-4 (Sterile), 5 (Twisted leaf), 7 (Narrow leaf), 8 (Rolled leaf), 9 (Stout), 10 (Short grain), 11 (Pseudonormal) and 12 (Tall) were isolated, each of which exhibited several distinct morphological features. Among the 505 PMCs analysed, 79.80 % had 12II, 5.45 % had 11II and 1.78 % PMCs had 1III configurations. The size of the extra chromosome was found to be smaller than those of O. sativa chromosomes and in 97.25 % of PMCs it remained unpaired and at a distance from the rest of the chromosomes. Of the 8 MAALs screened for YSB resistance, MAAL 11 was found to be moderately resistant. Undesirable morphological traits of O. brachyantha were found to be eliminated in the MAALs.Not Availabl

Generation of a FMR1 homozygous knockout human embryonic stem cell line (WAe009-A-16) by CRISPR/Cas9 editing.

Mutations in FMR1 gene is the cause of Fragile X Syndrome (FXS) leading inherited cause of intellectual disability and autism spectrum disorders. FMR1 gene encodes Fragile X Mental Retardation Protein (FMRP) which is a RNA binding protein and play important role in synaptic plasticity and translational regulation in neurons. We have generated a homozygous FMR1 knockout (FMR1-KO) hESC line using CRISPR/Cas9 based genome editing. It created a homozygous 280 nucleotide deletion at exon1, removing the start codon. This FMR1-KO cell line maintains stem cell like morphology, pluripotency, normal karyotype and ability to in-vitro differentiation

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Not AvailableOryza brachyantha, the African wild rice which is resistant to yellow stem borer (YSB), was exploited as a source for introgression of YSB resistance trait into cultivated rice (O. sativa), through development of monosomic alien addition lines (MAALs). BC2F1 backcross hybrids (O. sativa cv Savitri/O. brachyantha//O. sativa cv Savitri/// O. sativa cv Savitri) were produced employing embryo rescue, with a crossability of 0.12 %. Hybrid embryos that were collected at 10 and 12 days after pollination showed highest percentage of survival in culture with a germination percentage of 35.8 %. Cytological analysis of pollen mother cells (PMCs) of the BC2F1 hybrids revealed 15 hybrids with 2n ? 1(2n = 25) chromosome number that exhibited typical trisomic chromosomal configurations. These aneuploids were putatively designated as MAALs and characterized morphologically and cytologically. Based on their morphological similarity to primary trisomics of the cultivated rice (O. sativa), 8 MAALs viz., MAALs-4 (Sterile), 5 (Twisted leaf), 7 (Narrow leaf), 8 (Rolled leaf), 9 (Stout), 10 (Short grain), 11 (Pseudonormal) and 12 (Tall) were isolated, each of which exhibited several distinct morphological features. Among the 505 PMCs analysed, 79.80 % had12II, 5.45 % had 11II and 1.78 % PMCs had 1III configurations. The size of the extra chromosome was found to be smaller than those of O. sativa chromosomes and in 97.25 % of PMCs it remained unpaired and at a distance from the rest of the chromosomes. Of the 8 MAALs screened for YSB resistance, MAAL 11 was found to be moderately resistant. Undesirable morphological traits of O. brachyantha were found to be eliminated in the MAALs.Not Availabl

Deletion analysis of spinal muscular atrophy in southern Indian population

Background: Proximal spinal muscular atrophy (SMA) is a genetically heterogeneous disease with paresis and muscle atrophy due to loss of anterior horn cell function. The survival of motor neuron gene (SMN) and neuronal apoptosis inhibitory protein (NAIP) play a primary role. Both the gene homologues exist as inverted duplications on Chromosome 5q. The telomeric/functional (SMN1) and the centromeric (SMN2) copies differ from each other in eight nucleotides. The C→T transition (at Codon 280) within Exon 7 of SMN2 causes disruption of an exonic splicing enhancer (ESE) and/or creates an exonic splicing silencer (ESS) leading to abnormal splicing and a truncated protein. Objective: To determine the molecular genetics of SMN1 and NAIP genes in SMA from southern India. Materials and Methods: In the present study, 37 patients from the neuromuscular disorders clinic of National Institute of Mental Health and Neurosciences were assayed for the deletions in the SMN1 and NAIP genes using PCR-RFLP methods. Results: Among the SMA Type I patients, 43% showed deletions of SMN1 and NAIP. In patients Type II SMA, 57% showed deletions of the SMN1 exons. Conclusion: Thus, deletions were found to occur in 47.8% of the Type I and II patients. Lower sensitivity of gene deletion study in clinically suspected SMA needs further study as clinical diagnosis of SMA is not gold standard. However, the results do correlate with other studies conducted in India