Zia Choudhry

Sonic hedgehog signalling pathway: a complex network

Sonic Hedgehog (Shh) signalling cascade is one of the intricate signal transduction mechanisms that govern the precisely regulated developmental processes of multicellular organisms. Along with establishing the patterns of cellular differentiation to direct complex organ formation, it also has an important role in post-embryonic tissue regeneration and repair processes. Especially, Shh signalling is implicated in the induction of multifarious neuronal populations in central nervous system. There is compelling evidence of the involvement of Shh protein in the signalling network that regulates various morphogenetic processes such as the exquisite neural tube pattern formation. In the morphogenetic field, the activation of Shh signalling processes is intricately linked to the alterations at the molecular level in the structure of Shh protein that leads to its altered biophysical and biochemical reactivity. This brief article gives an overview of such complex cascade of events in Shh signalling and its transduction pathways.

LPHN3 and attention-deficit/hyperactivity disorder: interaction with maternal stress during pregnancy

BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous behavioral disorder, complex both in etiology and clinical expression. Both genetic and environmental factors have been implicated, and it has been suggested that gene-environment interactions may play a pivotal role in the disorder. Recently, a significant association was reported between ADHD and LPHN3 (which codes for latrophilin 3), and replicated in independent samples. METHODS We have examined the association between tag single nucleotide polymorphisms (SNPs) in LPHN3 within the region previously implicated in ADHD. Family based association tests (FBAT) were conducted (n = 380 families) with the categorical diagnosis of ADHD, behavioral and cognitive phenotypes related to ADHD, and response to treatment (given a fixed dose of methylphenidate, 0.5 mg/day). Stratified FBAT analyses, based on maternal smoking and stress during pregnancy, was conducted. RESULTS Whereas limited association was observed in the total sample, highly significant interaction between four LPHN3 tag SNPs (rs6551665, rs1947274, rs6858066, rs2345039) and maternal stress during pregnancy was noted. Analysis conducted in the sub-group of mothers exposed to minimal stress during pregnancy showed significant associations with ADHD, behavioral and cognitive dimensions related to ADHD, as well as treatment response. Although extensive association was observed with the candidate SNPs, the findings are partially inconsistent with previously published results with the opposite alleles over-transmitted in these studies. CONCLUSIONS These results provide evidence for the interaction between a genetic and environmental factor independently shown to be associated with ADHD. If confirmed in independent large studies, they may present a step forward in unraveling the complex etiology of ADHD.

Association between obesity‐related gene FTO and ADHD

Attention‐deficit/hyperactivity disorder (ADHD) is an etiologically complex heterogeneous behavioral disorder. Several studies have reported that ADHD subjects are more likely to be overweight/obese and that this comorbidity may be due to shared genetic factors. The objective of this study is to explore the association between ADHD and FTO, a gene strongly associated with obesity in genome‐wide studies.

A critique of the literature on etiology of eating disorders.

The development of eating disorders including anorexia nervosa, bulimia nervosa, binge eating disorder, and atypical eating disorders that affect many young women and even men in the productive period of their lives is complex and varied. While numbers of presumed risk factors contributing to the development of eating disorders are increasing, previous evidence for biological, psychological, developmental, and sociocultural effects on the development of eating disorders have not been conclusive. Despite the fact that a huge body of research has carefully examined the possible risk factors associated with the eating disorders, they have failed not only to uncover the exact etiology of eating disorders, but also to understand the interaction between different causes of eating disorders. This failure may be due complexities of eating disorders, limitations of the studies or combination of two factors. In this review, some risk factors including biological, psychological, developmental, and sociocultural are discussed.

Body weight and ADHD: examining the role of self-regulation.

Objective Attention-Deficit/Hyperactivity Disorder (ADHD) is a complex and heterogeneous childhood disorder that often coexists with other psychiatric and somatic disorders. Recently, a link between ADHD and body weight dysregulation has been reported and often interpreted as impaired self-regulation that is shared between the two conditions. The objective of this study is to investigate the relation between body weight/BMI and cognitive, emotional and motor characteristics in children with ADHD. Methods 284 ADHD children were stratified by weight status/BMI according to WHO classification and compared with regard to their neurocognitive characteristics, motivational style, and motor profile as assessed by a comprehensive battery of tests. All comparisons were adjusted for demographic characteristics of relevance including, socioeconomic status (SES). Results Both Obese and overweight ADHD children exhibited significantly lower SES compared to normal weight ADHD children. No significant differences were observed between the three groups with regards to their neurocognitive, emotional and motor profile. Conclusions Our findings provide evidence that differences in weight/BMI are not accounted for by cognitive, motivational and motor profiles. Socio-economic characteristics are strongly associated with overweight and obesity in ADHD children and may inform strategies aimed at promoting healthier weight.

Comprehensive Phenotype/Genotype Analyses of the Norepinephrine Transporter Gene (SLC6A2) in ADHD: Relation to Maternal Smoking during Pregnancy

Objective Despite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD. Methods Children (6–12 years old) diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH) using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT), including categorical and quantitative trait analyses, were conducted in 377 nuclear families. Results A highly significant association was observed with rs36021 (and linked SNPs) in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis (Z = 3.74, P = 0.0002), behavioral assessments by parents (CBCL, P = 0.00008), as well as restless-impulsive subscale scores on Conners’-teachers (P = 0.006) and parents (P = 0.006). In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff (Z = 3.28, P = 0.001), parents (Z = 2.62, P = 0.009), as well as evaluation in the simulated academic environment (Z = 3.58, P = 0.0003). Conclusions By using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within SLC6A2 and ADHD diagnosis, behavioral and cognitive measures relevant to ADHD and response to MPH. This comprehensive phenotype/genotype analysis may help to further understand this complex disorder and improve its treatment. Clinical trial registration information – Clinical and Pharmacogenetic Study of Attention Deficit with Hyperactivity Disorder (ADHD); www.clinicaltrials.gov; NCT00483106.

The mechanism of degeneration of striatal neuronal subtypes in Huntington disease

The pattern of neurodegeneration in Huntington’s disease (HD) is very characteristic of regional locations as well as that of neuronal types in striatum. The different striatal neuronal populations demonstrate different degree of degeneration in response to various pathological events in HD. In the striatum, medium spiny GABA neurons (MSN) are preferentially degenerate while others are relatively spared. Vulnerability of specific neuronal populations within the striatum to pathological events constitutes an important hallmark of degeneration in HD. In an attempt to explain a likely mechanism of degeneration of striatal neuronal populations in HD, possible causes underlying differential vulnerability of neuronal subtypes to excitoxic insults and neurotrophic factors are discussed in this paper.

TCF4 gene polymorphism and cognitive performance in patients with first episode psychosis.

BACKGROUND Single nucleotide polymorphisms in TCF4 gene have been consistently associated with schizophrenia in genome wide association studies, including the C allele of rs9960767. However, its exact role in modulating the schizophrenia phenotype is not known. AIMS To comprehensively investigate the relationship between rs9960767 risk allele (C) of TCF4 and cognitive performance in patients with first episode psychosis (FEP). METHODS 173 patients with FEP received a comprehensive neurocognitive evaluation and were genotyped for rs9960767. Carriers of the risk allele (CA/CC) were compared to non-carriers (AA) using Multivariate Analysis of Covariance MANCOVA. Ethnicity, negative symptoms and substance abuse were included as covariates. RESULTS Carriers of the risk allele had a statistically significant lower performance in the cognitive domain of Reasoning/Problem-Solving compared to non-carriers (F1,172=4.4, p=.038). There were no significant genotype effects on the other cognitive domains or general cognition. This effect on the Reasoning/Problem-Solving domain remained significant even when controlling for IQ (F1,172=4.3, p=.039). CONCLUSIONS rs9960767 (C) of TCF4 appears to be associated with neurocognitive deficits in the Reasoning/Problem-Solving cognitive domain, in patients with FEP. A confirmation of this finding in a larger sample and including other TCF4 polymorphisms will be needed to gain further validity of this result.

Catechol-o-methyltransferase gene and executive function in children with ADHD.

Objective: To examine the association between functional haplotypes in the catechol-o-methyltransferase (COMT) gene and ADHD diagnosis, and executive function (EF) in children with ADHD. Method: COMT single nucleotide polymorphism (SNPs; rs6269, rs4633, rs4818, and rs4680) were genotyped in 445 ADHD children. EF was assessed using Wisconsin Card Sorting Test (WCST), Tower of London, and self-ordered pointing task. COMT haplotypes were tested for association using family-based association testing (fBAT) and quantitative trait analyses. Results: fBAT analysis showed no association between COMT alleles/haplotypes and ADHD diagnosis and EF parameters. Using ANCOVA in the Caucasian only sample, significant associations between COMT haplotypes, and WCST indices were observed. However, after correction for multipletesting, the only significant effect observed was between rs6269 and the number of categories completed (a measure of concept formation ability) on the WCST, F(1,285) = 8.92, p = .003. Conclusion: These results tentatively implicate COMT gene in modulating EF in children with ADHD.

Spatially regulated adult neurogenesis

Adult neurogenesis has been the center of attention for decades. Neuroscientists hope to understand the mechanism underlying this phenomenon that might provide a unique perception of brain repair in future. Neurogenesis is referred to the process in which neuronal stem cells and progenitors generate new neurons in non-pathologic setting. Although there are some similarities between two neurogenetic regions including hippocampus and olfactory bulb, however there are some important differences. Regardless of the unique functional roles of ongoing neurogenesis in olfactory bulb and hippocampus, the differences are in terms of consequence of neurogenesis, origin of newly born neurons, responding receptors to nicotine exposure, neuronal migration and GABAergic input between two regions. In this paper, we have briefly reviewed the differences of adult neurogenesis between olfactory bulb and hippocampus.