期刊
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS
卷 171, 期 3, 页码 333-341出版社
WILEY-BLACKWELL
DOI: 10.1002/ajmg.b.32408
关键词
major depressive disorder; whole-exome analysis; psychiatric disorders; transcription factors; gene ontology
资金
- Brain and Behavior Research Foundation [17832]
- NIH [R01 MH036197, P50 MH090966, U01 MH099225, R01 NS 061829-04, T32-MH65213]
- Sackler Institute for Developmental Psychobiology
- Nationwide Children's Hospital, Columbus, OH
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 Zn2+ 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 variantencoding a non-conservative P17R substitution in the conserved repressor domain of ZNF34 proteinsegregating 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. (c) 2016 Wiley Periodicals, Inc.
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