Dataset Information

Highly penetrant alterations of a critical region including BDNF in human psychopathology and obesity.

ABSTRACT: CONTEXT Brain-derived neurotrophic factor (BDNF) is suspected of being a causative factor in psychiatric disorders based on case reports or studies involving large structural anomalies. OBJECTIVE To determine the involvement of BDNF in human psychopathology. DESIGN Case-control study. SETTING Microarray-based comparative genomic hybridization data from 7 molecular diagnostic centers including 38 550 affected subjects and 28 705 unaffected subjects. PATIENTS Subjects referred to diagnostic screening centers for microarray-based comparative genomic hybridization for physical or cognitive impairment. MAIN OUTCOME MEASURES Genomic copy number gains and losses. RESULTS We report 5 individuals with psychopathology and genomic deletion of a critical region including BDNF. The defined critical region was never disrupted in control subjects or diagnostic cases without developmental abnormalities. CONCLUSION Hemizygosity of the BDNF region contributes to variable psychiatric phenotypes including anxiety, behavioral, and mood disorders.

SUBMITTER: Ernst C

PROVIDER: S-EPMC3590016 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Highly penetrant alterations of a critical region including BDNF in human psychopathology and obesity.

Ernst Carl C Marshall Christian R CR Shen Yiping Y Metcalfe Kay K Rosenfeld Jill J Hodge Jennelle C JC Torres Alcy A Blumenthal Ian I Chiang Colby C Pillalamarri Vamsee V Crapper Liam L Diallo Alpha B AB Ruderfer Douglas D Pereira Shahrin S Sklar Pamela P Purcell Shaun S Wildin Robert S RS Spencer Anne C AC Quade Bradley F BF Harris David J DJ Lemyre Emanuelle E Wu Bai-Lin BL Stavropoulos Dimitri J DJ Geraghty Michael T MT Shaffer Lisa G LG Morton Cynthia C CC Scherer Stephen W SW Gusella James F JF Talkowski Michael E ME

Archives of general psychiatry 20121201 12

CONTEXT Brain-derived neurotrophic factor (BDNF) is suspected of being a causative factor in psychiatric disorders based on case reports or studies involving large structural anomalies. OBJECTIVE To determine the involvement of BDNF in human psychopathology. DESIGN Case-control study. SETTING Microarray-based comparative genomic hybridization data from 7 molecular diagnostic centers including 38 550 affected subjects and 28 705 unaffected subjects. PATIENTS Subjects referred to diagnostic screen ...[more]

PMID: 23044507

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Project description:Significant human diseases/phenotypes exist which require both an environmental trigger event and a genetic predisposition before the disease/phenotype emerges, e.g. Carbamazepine with the rare SNP allele of rs3909184 causing Stevens Johnson syndrome, and aminoglycosides with rs267606617 causing sensory neural deafness. The underlying genotypes are fully penetrant only when the correct environmental trigger(s) occur, otherwise they are silent and harmless. Such diseases/phenotypes will not appear to have a Mendelian inheritance pattern, unless the environmental trigger is very common (>50% per lifetime). The known causative genotypes are likely to be protein-altering SNPs with dominant/semi-dominant effect. We questioned whether other diseases and phenotypes could have a similar aetiology.We wrote the fSNPd program to analyse multiple exomes from a test cohort simultaneously with the purpose of identifying SNP alleles at a significantly different frequency to that of the general population. fSNPd was tested on trial cohorts, iteratively improved, and modelled for performance against an idealised association study under mutliple parameters. We also assessed the seqeuncing depath of all human exons to determine which were sufficiently well sequenced in an exome to be sued by fSNPd - by assessing forty exomes base by base.We describe a simple methodology for the detection of SNPs capable of causing a phenotype triggered by an environmental event. This uses cohorts of relatively small size (30-100 individuals) with the phenotype being investigated, their exomes, and thence seeks SNP allele frequencies significantly different from expected to identify potentially clinically important, protein altering SNP alleles. The strengths and weaknesses of this approach for discovering significant genetic causes of human disease are comparable to Mendelian disease mutation detection and Association Studies.The fSNPd methodology is another approach, and has potentially significant advantage over Association studies in needing far fewer individuals, to detect genes involved in the pathogenesis of a diseases/phenotypes. Furthermore, the SNP alleles identified alter amino acids, potentially making it easier to devise functional assays of protein function to determine pathogenicity.

Dataset Information

Highly penetrant alterations of a critical region including BDNF in human psychopathology and obesity.

Publications

Highly penetrant alterations of a critical region including BDNF in human psychopathology and obesity.

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