Novel variants in ZNF34 and other brain-expressed transcription factors are shared among early-onset MDD relatives.
Am J Med Genet B Neuropsychiatr Genet
; 171B(3): 333-41, 2016 Apr.
Article
en En
| MEDLINE
| ID: mdl-26823146
ABSTRACT
There are no known genetic variants with large effects on susceptibility to major depressive disorder (MDD). Although one proposed study approach is to increase sensitivity by increasing sample sizes, another is to focus on families with multiple affected individuals to identify genes with rare or novel variants with strong effects. Choosing the family-based approach, we performed whole-exome analysis on affected individuals (n = 12) across five MDD families, each with at least five affected individuals, early onset, and prepubertal diagnoses. We identified 67 genes where novel deleterious variants were shared among affected relatives. Gene ontology analysis shows that of these 67 genes, 18 encode transcriptional regulators, eight of which are expressed in the human brain, including four KRAB-A box-containing Zn(2+) finger repressors. One of these, ZNF34, has been reported as being associated with bipolar disorder and as differentially expressed in bipolar disorder patients compared to healthy controls. We found a novel variant-encoding a non-conservative P17R substitution in the conserved repressor domain of ZNF34 protein-segregating completely with MDD in all available individuals in the family in which it was discovered. Further analysis showed a common ZNF34 coding indel segregating with MDD in a separate family, possibly indicating the presence of an unobserved, linked, rare variant in that particular family. Our results indicate that genes encoding transcription factors expressed in the brain might be an important group of MDD candidate genes and that rare variants in ZNF34 might contribute to susceptibility to MDD and perhaps other affective disorders.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
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Familia
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Polimorfismo de Nucleótido Simple
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Factores Generales de Transcripción
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Trastorno Depresivo Mayor
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Proteínas de Unión al ADN
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Am J Med Genet B Neuropsychiatr Genet
Asunto de la revista:
GENETICA MEDICA
/
NEUROLOGIA
/
PSIQUIATRIA
Año:
2016
Tipo del documento:
Article