Bipolar disorder with comorbid binge eating history: A genome-wide association study implicates APOB

Winham, Stacey J.; Cuellar-Barboza, Alfredo B.; McElroy, Susan L.; Oliveros, Alfredo; Crow, Scott J.; Colby, Colin; Choi, Doo Sup; Chauhan, Monika; Frye, Mark A.; Biernacka, Joanna M.

doi:10.1016/j.jad.2014.04.026

Cited by 39 publications

(37 citation statements)

References 50 publications

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“…In the brain, mTOR is important for neuronal development, synaptic plasticity, and axonal regeneration and limits astrocytic scar formation [46]. PRR5 was recently associated to bipolar disorder [47]. The PRR12 mRNA was also identified as a target of FMRP [27].…”

Section: Discussionmentioning

confidence: 99%

A de novo t(10;19)(q22.3;q13.33) leads to ZMIZ1/PRR12 reciprocal fusion transcripts in a girl with intellectual disability and neuropsychiatric alterations

et al. 2015

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We report a girl with intellectual disability (ID), neuropsychiatric alterations, and a de novo balanced t(10;19)(q22.3;q13.33) translocation. After chromosome sorting, fine mapping of breakpoints by array painting disclosed disruptions of the zinc finger, MIZ-type containing 1 (ZMIZ1) (on chr10) and proline-rich 12 (PRR12) (on chr19) genes. cDNA analyses revealed that the translocation resulted in gene fusions. The resulting hybrid transcripts predict mRNA decay or, if translated, formation of truncated proteins, both due to frameshifts that introduced premature stop codons. Though other molecular mechanisms may be operating, these results suggest that haploinsufficiency of one or both genes accounts for the patient's phenotype. ZMIZ1 is highly expressed in the brain, and its protein product appears to interact with neuron-specific chromatin remodeling complex (nBAF) and activator protein 1 (AP-1) complexes which play a role regulating the activity of genes essential for normal synapse and dendrite growth/behavior. Strikingly, the patient's phenotype overlaps with phenotypes caused by mutations in SMARCA4 (BRG1), an nBAF subunit presumably interacting with ZMIZ1 in brain cells as suggested by our results of coimmunoprecipitation in the mouse brain. PRR12 is also expressed in the brain, and its protein product possesses domains and residues thought to be related in formation of large protein complexes and chromatin remodeling. Our observation from E15 mouse brain cells that a Prr12 isoform was confined to nucleus suggests a role as a transcription nuclear cofactor likely involved in neuronal development. Moreover, a pilot transcriptome analysis from t(10;19) lymphoblastoid cell line suggests dysregulation of genes linked to neurodevelopment processes/neuronal communication (e.g., NRCAM) most likely induced by altered PRR12. This case represents the first constitutional balanced translocation disrupting and fusing both genes and provides clues for the potential function and effects of these in the central nervous system.

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Section: Discussionmentioning

confidence: 99%

A de novo t(10;19)(q22.3;q13.33) leads to ZMIZ1/PRR12 reciprocal fusion transcripts in a girl with intellectual disability and neuropsychiatric alterations

et al. 2015

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“…For mtSNPs showing the strongest associations based on the joint tests, genome-wide analyses were repeated using imputed SNP data to generate Manhattan plots and locus zoom plots. Genome-wide imputation for the GAIN BD data was conducted using the 1,000 Genome Project cosmopolitan reference panel, and the detailed procedures have been previously described [44]. …”

Section: Methodsmentioning

confidence: 99%

A Genome-Wide Search for Bipolar Disorder Risk Loci Modified by Mitochondrial Genome Variation

et al. 2017

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Mitochondrial DNA mutations have been reported to be associated with bipolar disorder (BD). In this study, we performed genome-wide analyses to assess mitochondrial single-nucleotide polymorphism (mtSNP) effects on BD risk and early-onset BD (EOBD) among BD patients, focusing on interaction effects between nuclear SNPs (nSNPs) and mtSNPs. Common nSNP and mtSNP data from European American BD cases (n = 1,001) and controls (n = 1,034) from the Genetic Association Information Network BD study were analyzed to assess the joint effect of nSNP and nSNP-mtSNP interaction on the risk of BD and EOBD. The effect of nSNP-mtSNP interactions was also assessed. For BD risk, the strongest evidence of an association was obtained for nSNP rs1880924 in MGAM and mtSNP rs3088309 in CytB (p_joint = 8.2 × 10^-8, p_int = 1.4 × 10^-4). Our results also suggest that the minor allele of the nSNP rs583990 in CTNNA2 increases the risk of EOBD among carriers of the mtSNP rs3088309 minor allele, while the nSNP has no effect among those carrying the mtSNP major allele (OR = 4.53 vs. 1.05, p_joint = 2.1 × 10^-7, p_int = 1.16 × 10^-6). While our results are not statistically significant after multiple testing correction and a large-sample replication is required, our exploratory study demonstrates the potential importance of considering the mitochondrial genome for identifying genetic factors associated with BD.

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“…Unsurprisingly, several modestly powered GWAS studies for ED-related traits reported negative findings after correcting for multiple testing [79,80]. A recent negative two-stage GWAS meta-analysis for AN in 5,551 cases and 21,080 controls concluded that the accrual of large genotyped AN case-control samples should be an immediate priority for the field to identify AN-predisposing genes [81].…”

Section: Genome-wide Association Studiesmentioning

confidence: 99%

“…The only genomewide CNV study of EDs reported a 1.4-Mb deletion on 13q12 in 2 AN cases [80]. A genome-wide search for copy-number variants associated with BMI, found a 600-Kb deletion on chromosome 16p11.2 associated with a highly penetrant form of obesity accompanied by hyperphagia and increased ad libitum food intake [92,93].…”

Section: Copy Number Variantsmentioning

confidence: 99%

An Evolutionary Genetic Perspective of Eating Disorders

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et al. 2017

Neuroendocrinology

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Eating disorders (ED) including anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED) affect up to 5% of the population in Western countries. Risk factors for developing an ED include personality traits, family environment, gender, age, ethnicity, and culture. Despite being moderately to highly heritable with estimates ranging from 28 to 83%, no genetic risk factors have been conclusively identified. Our objective was to explore evolutionary theories of EDs to provide a new perspective on research into novel biological mechanisms and genetic causes of EDs. We developed a framework that explains the possible interactions between genetic risk and cultural influences in the development of ED. The framework includes three genetic predisposition categories (people with mainly AN restrictive gene variants, people with mainly BED variants, and people with gene variants predisposing to both diseases) and a binary variable of either the presence or absence of pressure to be thin. We propose novel theories to explain the overlapping characteristics of the subtypes of AN (binge/purge and restrictive), BN, and BED. For instance, mutations/structural gene variants in the same gene causing opposite effects or mutations in nearby genes resulting in partial disequilibrium for the genes causing AN (restrictive) and BED may explain the overlap of phenotypes seen in AN (binge/purge).

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Bipolar disorder with comorbid binge eating history: A genome-wide association study implicates APOB

Cited by 39 publications

References 50 publications

A de novo t(10;19)(q22.3;q13.33) leads to ZMIZ1/PRR12 reciprocal fusion transcripts in a girl with intellectual disability and neuropsychiatric alterations

A de novo t(10;19)(q22.3;q13.33) leads to ZMIZ1/PRR12 reciprocal fusion transcripts in a girl with intellectual disability and neuropsychiatric alterations

A Genome-Wide Search for Bipolar Disorder Risk Loci Modified by Mitochondrial Genome Variation

An Evolutionary Genetic Perspective of Eating Disorders

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