Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder.
Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder.
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DOI：
10.1038/s41380-023-02096-x
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发表时间：
2023-10
影响因子：
11
通讯作者：
Kato, Tadafumi
中科院分区：
文献类型：
--
作者：
Nishioka, Masaki;Takayama, Jun;Sakai, Naomi;Kazuno, An-a;Ishiwata, Mizuho;Ueda, Junko;Hayama, Takashi;Fujii, Kumiko;Someya, Toshiyuki;Kuriyama, Shinichi;Tamiya, Gen;Takata, Atsushi;Kato, Tadafumi
Bipolar disorder (BD) is a global medical issue, afflicting around 1% of the population with manic and depressive episodes. Despite various genetic studies, the genetic architecture and pathogenesis of BD have not been fully resolved. Besides germline variants, postzygotic mosaic variants are proposed as new candidate mechanisms contributing to BD. Here, we performed extensive deep exome sequencing (DES, ~300×) and validation experiments to investigate the roles of mosaic variants in BD with 235 BD cases (194 probands of trios and 41 single cases) and 39 controls. We found an enrichment of developmental disorder (DD) genes in the genes hit by deleterious mosaic variants in BD (P = 0.000552), including a ClinVar-registered pathogenic variant in ARID2. An enrichment of deleterious mosaic variants was also observed for autism spectrum disorder (ASD) genes (P = 0.000428). The proteins coded by the DD/ASD genes with non-synonymous mosaic variants in BD form more protein-protein interaction than expected, suggesting molecular mechanisms shared with DD/ASD but restricted to a subset of cells in BD. We also found significant enrichment of mitochondrial heteroplasmic variants, another class of mosaic variants, in mitochondrial tRNA genes in BD (P = 0.0102). Among them, recurrent m.3243 A > G variants known as causal for mitochondrial diseases were found in two unrelated BD probands with allele fractions of 5–12%, lower than in mitochondrial diseases. Despite the limitation of using peripheral tissues, our DES investigation supports the possible contribution of deleterious mosaic variants in the nuclear genome responsible for severer phenotypes, such as DD/ASD, to the risk of BD and further demonstrates that the same paradigm can be applied to the mitochondrial genome. These results, as well as the enrichment of heteroplasmic mitochondrial tRNA variants in BD, add a new piece to the understanding of the genetic architecture of BD and provide general insights into the pathological roles of mosaic variants in human diseases.
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DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
64.8
作者：
GOTO, Y;NONAKA, I;HORAI, S
通讯作者：
HORAI, S
影响因子：
5.3
作者：
Snijders Blok L;Hiatt SM;Bowling KM;Prokop JW;Engel KL;Cochran JN;Bebin EM;Bijlsma EK;Ruivenkamp CAL;Terhal P;Simon MEH;Smith R;Hurst JA;DDD study;McLaughlin H;Person R;Crunk A;Wangler MF;Streff H;Symonds JD;Zuberi SM;Elliott KS;Sanders VR;Masunga A;Hopkin RJ;Dubbs HA;Ortiz-Gonzalez XR;Pfundt R;Brunner HG;Fisher SE;Kleefstra T;Cooper GM
通讯作者：
Cooper GM
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
6.8
作者：
Fullard, John F.;Charney, Alexander W.;Roussos, Panos
通讯作者：
Roussos, Panos