Abhishek Bhandari

Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.

Microduplications of 16p11.2 are associated with schizophrenia.

Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 × 10−5, OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 × 10−7), bipolar disorder (P = 0.017) and autism (P = 1.9 × 10−7). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 × 10−13). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

Whole-Genome Sequencing in Autism Identifies Hot Spots for De Novo Germline Mutation

De novo mutation plays an important role in autism spectrum disorders (ASDs). Notably, pathogenic copy number variants (CNVs) are characterized by high mutation rates. We hypothesize that hypermutability is a property of ASD genes and may also include nucleotide-substitution hot spots. We investigated global patterns of germline mutation by whole-genome sequencing of monozygotic twins concordant for ASD and their parents. Mutation rates varied widely throughout the genome (by 100-fold) and could be explained by intrinsic characteristics of DNA sequence and chromatin structure. Dense clusters of mutations within individual genomes were attributable to compound mutation or gene conversion. Hypermutability was a characteristic of genes involved in ASD and other diseases. In addition, genes impacted by mutations in this study were associated with ASD in independent exome-sequencing data sets. Our findings suggest that regional hypermutation is a significant factor shaping patterns of genetic variation and disease risk in humans.

Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia

Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and 22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2–4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs.

Helicobacter pylori in Gastric Malignancies

Helicobacter pylori infection remains common worldwide and is significantly associated with gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT)lymphoma. This article reviews recent developments in the field of H. pylori with an emphasis on mechanisms of carcinogenesis, and the bacterial, environmental and host factors that may alter risk of developing gastric cancer or gastric MALT lymphoma. The topic of eradication of H. pylori to prevent the development of malignancy and the possibility of a vaccine against H. pylori are also explored.

Frequency and Complexity of De Novo Structural Mutation in Autism

Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.

Mo1136 Colorectal Cancer Under Age 50 Years: a Surveillance Epidemiology and End Results Based Analysis of CRC Incidence and Mortality in Young Adults Overall, Stratified by Sex, and Relative to Other Common Cancers

Background: Colorectal cancer (CRC) is a leading cause of cancer death worldwide, accounting for 608,000 deaths in 2008 (World Health Organization, 2013). Largely as a result of screening, CRC incidence is declining, but the trend is restricted to individuals age >50 years (Edwards BK 2010). Indeed, CRC incidence is increasing among individuals younger than 50 (World Health Organization, 2013; Siegel RL 2009). Setting public health priorities for screening research and interventions requires understanding absolute rates of CRC incidence and mortality, and assessment of CRC incidence and mortality relative to other cancer types. Our aim was to use population-based cancer registry data to contrast CRC incidence and mortality relative to other common cancers, overall, and by sex. Methods: We utilized the Surveillance, Epidemiology, and End Results [SEER] Cancer Query system to obtain cancer incidence and mortality data from the SEER Registry 20012010. To compare cancer site-specific mortality rates, we extracted age-adjusted mortality per 100,000 for individuals aged 20-44 years. To compare cancer site-specific incidence rates, we extracted age-specific incidence per 100,000 for individuals aged 15-49 years. We present mortality and incidence data for the common young-onset cancers overall as well as stratified by sex. Results: Figure 1 demonstrates that CRC is the 3rd leading cause of cancer death among young adults, after breast and lung cancer, at 1.67 cases per 100,000. Among males under age 45 yrs, CRC was the 2nd leading cause of cancer death, at 1.82 cases per 100,000, 2nd only to lung cancer. Among females under age 45 yrs, CRC was the 4th leading cause of cancer death, at 1.51 per 10000, behind breast, lung, and cervical cancer, respectively. Sexspecific differences in young onset CRC incidence patterns were noted. Among males, CRC became the 2nd most incident cancer after age 30, with 4.9, 9.0, 16.4, and 30.8 cases per 100,000 for ages 30-34, 35-39, 40-44, and 45-49 yrs, respectively (Figure 2A). Among females, CRC incidence patterns were similar to males after age 30, with 4.2, 7.6, 15.3, and 25.9 cases per 100,000 for ages 30-34, 35-39, 40-44, and 45-49 yrs, respectively (Figure 2B). However, among females, CRC incidence was dwarfed by breast cancer incidence overall, and less distinct from other cancers as compared to males. Conclusions: CRC is a frequent cause of cancer incidence and mortality among young adults in the U.S. Given the overall incidence and mortality of CRC among young adults, and previously reported increasing trends in incidence, and availability of effective screening tests for CRC, new strategies for identifying young adults at risk for CRC who may be candidates for screening should be developed.