2022
An, U. ; Cai, N. ; Dahl, A. ; Sankararaman, S.
In: (26th International Conference on Research in Computational Molecular Biology, RECOMB 2022, 22-25 May 2022, San Diego, California, United States). 2022. 385-386 (Lect. Notes Comput. Sc. ; 13278 LNBI)
Biomedical datasets that aim to collect diverse phenotypic and genomic data across large numbers of individuals are plagued by the large fraction of missing data The ability to accurately impute or “fill-in” missing entries in these datasets is critical to a number of downstream applications.
Schork, A.J. ; Peterson, R.E. ; Dahl, A. ; Cai, N. ; Kendler, K.S.
Nat. Genet., DOI: 10.1038/s41588-022-01092-1 (2022)
In the version of this article initially published, the affiliations shown for Roseann E. Peterson were incorrect. The correct affiliation, “Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA,” has been updated in the HTML and PDF versions of the article.
Falkai, P. ; Koutsouleris, N. ; Bertsch, K. ; Bialas, M. ; Binder, E. ; Bühner, M. ; Buyx, A. ; Cai, N. ; Cappello, S. ; Ehring, T. ; Gensichen, J. ; Hamann, J. ; Hasan, A. ; Henningsen, P. ; Leucht, S. ; Möhrmann, K.H. ; Nagelstutz, E. ; Padberg, F. ; Peters, A. ; Pfäffel, L. ; Reich-Erkelenz, D. ; Riedl, V. ; Rueckert, D. ; Schmitt, A. ; Schulte-Körne, G. ; Scheuring, E. ; Schulze, T.G. ; Starzengruber, R. ; Stier, S. ; Theis, F.J. ; Winkelmann, J. ; Wurst, W. ; Priller, J.
Front. Psychiatr. 13:815718 (2022)
The Federal Ministry of Education and Research (BMBF) issued a call for a new nationwide research network on mental disorders, the German Center of Mental Health (DZPG). The Munich/Augsburg consortium was selected to participate as one of six partner sites with its concept "Precision in Mental Health (PriMe): Understanding, predicting, and preventing chronicity." PriMe bundles interdisciplinary research from the Ludwig-Maximilians-University (LMU), Technical University of Munich (TUM), University of Augsburg (UniA), Helmholtz Center Munich (HMGU), and Max Planck Institute of Psychiatry (MPIP) and has a focus on schizophrenia (SZ), bipolar disorder (BPD), and major depressive disorder (MDD). PriMe takes a longitudinal perspective on these three disorders from the at-risk stage to the first-episode, relapsing, and chronic stages. These disorders pose a major health burden because in up to 50% of patients they cause untreatable residual symptoms, which lead to early social and vocational disability, comorbidities, and excess mortality. PriMe aims at reducing mortality on different levels, e.g., reducing death by psychiatric and somatic comorbidities, and will approach this goal by addressing interdisciplinary and cross-sector approaches across the lifespan. PriMe aims to add a precision medicine framework to the DZPG that will propel deeper understanding, more accurate prediction, and personalized prevention to prevent disease chronicity and mortality across mental illnesses. This framework is structured along the translational chain and will be used by PriMe to innovate the preventive and therapeutic management of SZ, BPD, and MDD from rural to urban areas and from patients in early disease stages to patients with long-term disease courses. Research will build on platforms that include one on model systems, one on the identification and validation of predictive markers, one on the development of novel multimodal treatments, one on the regulation and strengthening of the uptake and dissemination of personalized treatments, and finally one on testing of the clinical effectiveness, utility, and scalability of such personalized treatments. In accordance with the translational chain, PriMe's expertise includes the ability to integrate understanding of bio-behavioral processes based on innovative models, to translate this knowledge into clinical practice and to promote user participation in mental health research and care.
Review
Review
Schork, A.J. ; Peterson, R.E. ; Dahl, A. ; Cai, N. ; Kendler, K.S.
Nat. Genet. 54, 372-373 (2022)
Editorial
Editorial
Nguyen, T.D. ; Harder, A. ; Xiong, Y. ; Kowalec, K. ; Hägg, S. ; Cai, N. ; Kuja-Halkola, R. ; Dalman, C. ; Sullivan, P.F. ; Lu, Y.
Mol. Psychiatry 27, 1667–1675 (2022)
Major depression (MD) is a heterogeneous disorder; however, the extent to which genetic factors distinguish MD patient subgroups (genetic heterogeneity) remains uncertain. This study sought evidence for genetic heterogeneity in MD. Using UK Biobank cohort, the authors defined 16 MD subtypes within eight comparison groups (vegetative symptoms, symptom severity, comorbid anxiety disorder, age at onset, recurrence, suicidality, impairment, and postpartum depression; N ~ 3000-47000). To compare genetic component of these subtypes, subtype-specific genome-wide association studies were performed to estimate SNP-heritability, and genetic correlations within subtype comparison and with other related disorders/traits. The findings indicated that MD subtypes were divergent in their SNP-heritability, and genetic correlations both within subtype comparisons and with other related disorders/traits. Three subtype comparisons (vegetative symptoms, age at onset, and impairment) showed significant differences in SNP-heritability; while genetic correlations within subtype comparisons ranged from 0.55 to 0.86, suggesting genetic profiles are only partially shared among MD subtypes. Furthermore, subtypes that are more clinically challenging, e.g., early-onset, recurrent, suicidal, more severely impaired, had stronger genetic correlations with other psychiatric disorders. MD with atypical-like features showed a positive genetic correlation (+0.40) with BMI while a negative correlation (-0.09) was found in those without atypical-like features. Novel genomic loci with subtype-specific effects were identified. These results provide the most comprehensive evidence to date for genetic heterogeneity within MD, and suggest that the phenotypic complexity of MD can be effectively reduced by studying the subtypes which share partially distinct etiologies.
Wissenschaftlicher Artikel
Scientific Article
Zou, J. ; Gopalakrishnan, S. ; Parker, C.C. ; Nicod, J. ; Mott, R. ; Cai, N. ; Lionikas, A. ; Davies, R.W. ; Palmer, A.A. ; Flint, J.
Genes Genomes Genetics G3 12:jkab394 (2022)
Combining samples for genetic association is standard practice in human genetic analysis of complex traits, but is rarely undertaken in rodent genetics. Here, using 23 phenotypes and genotypes from two independent laboratories, we obtained a sample size of 3,076 commercially available outbred mice and identified 70 loci, more than double the number of loci identified in the component studies. Fine-mapping in the combined sample reduced the number of likely causal variants, with a median reduction in set size of 51%, and indicated novel gene associations, including Pnpo, Ttll6 and GM11545 with bone mineral density, and Psmb9 with weight. However replication at a nominal threshold of 0.05 between the two component studies was low, with less than a third of loci identified in one study replicated in the second. In addition to overestimates in the effect size in the discovery sample (Winner's Curse), we also found that heterogeneity between studies explained the poor replication, but the contribution of these two factors varied among traits. Leveraging these observations we integrated information about replication rates, study-specific heterogeneity, and Winner's Curse corrected estimates of power to assign variants to one of four confidence levels. Our approach addresses concerns about reproducibility, and demonstrates how to obtain robust results from mapping complex traits in any genome-wide association study.
Wissenschaftlicher Artikel
Scientific Article
2021
Cai, N. ; Gomez-Duran, A. ; Yonova-Doing, E. ; Kundu, K. ; Burgess, A.I. ; Golder, Z.J. ; Calabrese, C. ; Bonder, M.J. ; Camacho, M. ; Lawson, R.A. ; Li, L. ; Williams-Gray, C.H. ; ICICLE-PD Study Group ; di Angelantonio, E. ; Roberts, D.J. ; Watkins, N.A. ; Ouwehand, W.H. ; Butterworth, A.S. ; Stewart, I.D. ; Pietzner, M. ; Wareham, N.J. ; Langenberg, C. ; Walter, K. ; Rothwell, P.M. ; Howson, J.M.M. ; Stegle, O. ; Chinnery, P.F. ; Soranzo, N.
Nat. Med. 27, 1564-1575 (2021)
Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis.
Wissenschaftlicher Artikel
Scientific Article
Bonder, M.J. ; Smail, C. ; Gloudemans, M.J. ; Frésard, L. ; Jakubosky, D. ; D'Antonio, M. ; Li, X. ; Ferraro, N.M. ; Carcamo-Orive, I. ; Mirauta, B. ; Seaton, D.D. ; Cai, N. ; Vakili, D. ; Horta, D. ; Zhao, C. ; Zastrow, D.B. ; Bonner, D.E. ; Wheeler, M.T. ; Kilpinen, H. ; Knowles, J.W. ; Smith, E.N. ; Frazer, K.A. ; Montgomery, S.B. ; Stegle, O.
Nat. Genet. 53, 313-321 (2021)
Induced pluripotent stem cells (iPSCs) are an established cellular system to study the impact of genetic variants in derived cell types and developmental contexts. However, in their pluripotent state, the disease impact of genetic variants is less well known. Here, we integrate data from 1,367 human iPSC lines to comprehensively map common and rare regulatory variants in human pluripotent cells. Using this population-scale resource, we report hundreds of new colocalization events for human traits specific to iPSCs, and find increased power to identify rare regulatory variants compared with somatic tissues. Finally, we demonstrate how iPSCs enable the identification of causal genes for rare diseases.
Wissenschaftlicher Artikel
Scientific Article
Chatzinakos, C. ; Lee, D. ; Cai, N. ; Vladimirov, V.I. ; Webb, B.T. ; Riley, B.P. ; Flint, J. ; Kendler, K.S. ; Ressler, K.J. ; Daskalakis, N.P. ; Bacanu, S.A.
Am. J. Med. Genet. B 196, 16-27 (2021)
Genotype imputation across populations of mixed ancestry is critical for optimal discovery in large-scale genome-wide association studies (GWAS). Methods for direct imputation of GWAS summary-statistics were previously shown to be practically as accurate as summary statistics produced after raw genotype imputation, while incurring orders of magnitude lower computational burden. Given that direct imputation needs a precise estimation of linkage-disequilibrium (LD) and that most of the methods using a small reference panel for example, ~2,500-subject coming from the 1000 Genome-Project, there is a great need for much larger and more diverse reference panels. To accurately estimate the LD needed for an exhaustive analysis of any cosmopolitan cohort, we developed DISTMIX2. DISTMIX2: (a) uses a much larger and more diverse reference panel compared to traditional reference panels, and (b) can estimate weights of ethnic-mixture based solely on Z-scores, when allele frequencies are not available. We applied DISTMIX2 to GWAS summary-statistics from the psychiatric genetic consortium (PGC). DISTMIX2 uncovered signals in numerous new regions, with most of these findings coming from the rarer variants. Rarer variants provide much sharper location for the signals compared with common variants, as the LD for rare variants extends over a lower distance than for common ones. For example, while the original PGC post-traumatic stress disorder GWAS found only 3 marginal signals for common variants, we now uncover a very strong signal for a rare variant in PKN2, a gene associated with neuronal and hippocampal development. Thus, DISTMIX2 provides a robust and fast (re)imputation approach for most psychiatric GWAS-studies.
Wissenschaftlicher Artikel
Scientific Article
2020
Chatzinakos, C. ; Georgiadis, F. ; Lee, D. ; Cai, N. ; Vladimirov, V.I. ; Docherty, A. ; Webb, B.T. ; Riley, B.P. ; Flint, J. ; Kendler, K.S. ; Daskalakis, N.P. ; Bacanu, S.A.
Am. J. Med. Genet. B 183, 454-463 (2020)
Genetic signal detection in genome-wide association studies (GWAS) is enhanced by pooling small signals from multiple Single Nucleotide Polymorphism (SNP), for example, across genes and pathways. Because genes are believed to influence traits via gene expression, it is of interest to combine information from expression Quantitative Trait Loci (eQTLs) in a gene or genes in the same pathway. Such methods, widely referred to as transcriptomic wide association studies (TWAS), already exist for gene analysis. Due to the possibility of eliminating most of the confounding effects of linkage disequilibrium (LD) from TWAS gene statistics, pathway TWAS methods would be very useful in uncovering the true molecular basis of psychiatric disorders. However, such methods are not yet available for arbitrarily large pathways/gene sets. This is possibly due to the quadratic (as a function of the number of SNPs) computational burden for computing LD across large chromosomal regions. To overcome this obstacle, we propose JEPEGMIX2-P, a novel TWAS pathway method that (a) has a linear computational burden, (b) uses a large and diverse reference panel (33 K subjects), (c) is competitive (adjusts for background enrichment in gene TWAS statistics), and (d) is applicable as-is to ethnically mixed-cohorts. To underline its potential for increasing the power to uncover genetic signals over the commonly used nontranscriptomics methods, for example,MAGMA, we applied JEPEGMIX2-P to summary statistics of most large meta-analyses from Psychiatric Genetics Consortium (PGC). While our work is just the very first step toward clinical translation of psychiatric disorders, PGC anorexia results suggest a possible avenue for treatment.
Wissenschaftlicher Artikel
Scientific Article
Cai, N. ; Choi, K.W. ; Fried, E.I.
Hum. Mol. Genet. 29, R10-R18 (2020)
With progress in genome-wide association studies (GWAS) of depression, from identifying zero hits in ~ 16 000 individuals in 2013 to 223 hits in more than a million individuals in 2020, understanding the genetic architecture of this debilitating condition no longer appears to be an impossible task. The pressing question now is whether recently discovered variants describe the etiology of a single disease entity. There are a myriad of ways to measure and operationalize depression severity, and major depressive disorder (MDD) as defined in the DSM-5 can manifest in more than ten thousand ways based on symptom profiles alone. Variations in developmental timing, comorbidity, and environmental contexts across individuals and samples further add to the heterogeneity. With big data increasingly enabling genomic discovery in psychiatry, it is more timely than ever to explicitly disentangle genetic contributions to what is likely 'depressions' rather than depression. Here, we introduce three sources of heterogeneity: operationalization, manifestation, and etiology. We review recent efforts to identify depression subtypes using clinical and data-driven approaches, examine differences in genetic architecture of depression across contexts, and argue that heterogeneity in operationalizations of depression is likely a considerable source of inconsistency. Finally, we offer recommendations and considerations for the field going forward.
Review
Review
Cai, N. ; Revez, J.A. ; Adams, M.J. ; Andlauer, T.F.M. ; Breen, G. ; Byrne, E.M. ; Clarke, T.K. ; Forstner, A.J. ; Grabe, H.J. ; Hamilton, S.P. ; Levinson, D.F. ; Lewis, C.M. ; Lewis, G. ; Martin, N.G. ; Milaneschi, Y. ; Mors, O. ; Müller-Myhsok, B. ; Penninx, B.W.J.H. ; Perlis, R.H. ; Pistis, G. ; Potash, J.B. ; Preisig, M. ; Shi, J. ; Smoller, J.W. ; Streit, F. ; Tiemeier, H. ; Uher, R. ; Van der Auwera, S. ; Viktorin, A. ; Weissman, M.M. ; Kendler, K.S. ; Flint, J.
Nat. Genet. 52, 437-447 (2020)
Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD): the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.Genetic analyses of depression based on minimal phenotyping identify nonspecific genetic risk factors shared between major depressive disorder (MDD) and other psychiatric conditions, suggesting that this approach may have limited ability to identify pathways specific to MDD.
Wissenschaftlicher Artikel
Scientific Article
2019
Dahl, A. ; Cai, N. ; Ko, A. ; Laakso, M. ; Pajukanta, P. ; Flint, J. ; Zaitlen, N.
PLoS Genet. 15:e1008009 (2019)
Recent and classical work has revealed biologically and medically significant subtypes in complex diseases and traits. However, relevant subtypes are often unknown, unmeasured, or actively debated, making automated statistical approaches to subtype definition valuable. We propose reverse GWAS (RGWAS) to identify and validate subtypes using genetics and multiple traits: while GWAS seeks the genetic basis of a given trait, RGWAS seeks to define trait subtypes with distinct genetic bases. Unlike existing approaches relying on off-the-shelf clustering methods, RGWAS uses a novel decomposition, MFMR, to model covariates, binary traits, and population structure. We use extensive simulations to show that modelling these features can be crucial for power and calibration. We validate RGWAS in practice by recovering a recently discovered stress subtype in major depression. We then show the utility of RGWAS by identifying three novel subtypes of metabolic traits. We biologically validate these metabolic subtypes with SNP-level tests and a novel polygenic test: the former recover known metabolic GxE SNPs; the latter suggests subtypes may explain substantial missing heritability. Crucially, statins, which are widely prescribed and theorized to increase diabetes risk, have opposing effects on blood glucose across metabolic subtypes, suggesting the subtypes have potential translational value.
Wissenschaftlicher Artikel
Scientific Article
2018
Cai, N. ; Revez, J.A. ; Adams, M.J. ; Andlauer, T.F.M. ; Breen, G. ; Byrne, E.M. ; Clarke, T.K. ; Forstner, A.J. ; Grabe, H.J. ; Hamilton, S.P. ; Levinson, D.F. ; Lewis, C.M. ; Lewis, G. ; Martin, N.G. ; Milaneschi, Y. ; Mors, O. ; Müller-Myhsok, B. ; Pennix, B.W.J.H. ; Perlis, R.H. ; Pistis, G. ; Potash, J.B. ; Preisig, M. ; Shi, J. ; Smoller, J.W. ; Streit, F. ; Tiemeier, H. ; Uher, R. ; Van der Auwera, S. ; Viktorin, A. ; Weissman, M.M.
bioRxiv, accepted (2018)
Minimal phenotyping refers to the reliance on the use of a small number of self-report items for disease case identification. This strategy has been applied to genome-wide association studies (GWAS) of major depressive disorder (MDD). Here we report that the genotype derived heritability (h2SNP) of depression defined by minimal phenotyping (14%, SE = 0.8%) is lower than strictly defined MDD (26%, SE = 2.2%). This cannot be explained by differences in prevalence between definitions or including cases of lower liability to MDD in minimal phenotyping definitions of depression, but can be explained by misdiagnosis of those without depression or with related conditions as cases of depression. Depression defined by minimal phenotyping is as genetically correlated with strictly defined MDD (rG = 0.81, SE = 0.03) as it is with the personality trait neuroticism (rG = 0.84, SE = 0.05), a trait not defined by the cardinal symptoms of depression. While they both show similar shared genetic liability with neuroticism, a greater proportion of the genome contributes to the minimal phenotyping definitions of depression (80.2%, SE = 0.6%) than to strictly defined MDD (65.8%, SE = 0.6%). We find that GWAS loci identified in minimal phenotyping definitions of depression are not specific to MDD: they also predispose to other psychiatric conditions. Finally, while highly predictive polygenic risk scores can be generated from minimal phenotyping definitions of MDD, the predictive power can be explained entirely by the sample size used to generate the polygenic risk score, rather than specificity for MDD. Our results reveal that genetic analysis of minimal phenotyping definitions of depression identifies non-specific genetic factors shared between MDD and other psychiatric conditions. Reliance on results from minimal phenotyping for MDD may thus bias views of the genetic architecture of MDD and may impede our ability to identify pathways specific to MDD.
Wissenschaftlicher Artikel
Scientific Article
Peterson, R.E. ; Cai, N. ; Dahl, A.W. ; Bigdeli, T.B. ; Edwards, A.C. ; Webb, B.T. ; Bacanu, S.A. ; Zaitlen, N. ; Flint, J. ; Kendler, K.S.
Am. J. Psychiatry 175, 545-554 (2018)
OBJECTIVE: The extent to which major depression is the outcome of a single biological mechanism or represents a final common pathway of multiple disease processes remains uncertain. Genetic approaches can potentially identify etiologic heterogeneity in major depression by classifying patients on the basis of their experience of major adverse events. METHOD: Data are from the China, Oxford, and VCU Experimental Research on Genetic Epidemiology (CONVERGE) project, a study of Han Chinese women with recurrent major depression aimed at identifying genetic risk factors for major depression in a rigorously ascertained cohort carefully assessed for key environmental risk factors (N=9,599). To detect etiologic heterogeneity, genome-wide association studies, heritability analyses, and gene-by-environment interaction analyses were performed. RESULTS: Genome-wide association studies stratified by exposure to adversity revealed three novel loci associated with major depression only in study participants with no history of adversity. Significant gene-by-environment interactions were seen between adversity and genotype at all three loci, and 13.2% of major depression liability can be attributed to genome-wide interaction with adversity exposure. The genetic risk in major depression for participants who reported major adverse life events (27%) was partially shared with that in participants who did not (73%; genetic correlation=+0.64). Together with results from simulation studies, these findings suggest etiologic heterogeneity within major depression as a function of environmental exposures. CONCLUSIONS: The genetic contributions to major depression may differ between women with and those without major adverse life events. These results have implications for the molecular dissection of major depression and other complex psychiatric and biomedical diseases.
Wissenschaftlicher Artikel
Scientific Article
2017
Speed, D. ; Cai, N. ; Johnson, M.R. ; Nejentsev, S. ; Balding, D.J.
Nat. Genet. 49, 986-992 (2017)
SNP heritability, the proportion of phenotypic variance explained by SNPs, has been reported for many hundreds of traits. Its estimation requires strong prior assumptions about the distribution of heritability across the genome, but current assumptions have not been thoroughly tested. By analyzing imputed data for a large number of human traits, we empirically derive a model that more accurately describes how heritability varies with minor allele frequency (MAF), linkage disequilibrium (LD) and genotype certainty. Across 19 traits, our improved model leads to estimates of common SNP heritability on average 43% (s.d. 3%) higher than those obtained from the widely used software GCTA and 25% (s.d. 2%) higher than those from the recently proposed extension GCTA-LDMS. Previously, DNase I hypersensitivity sites were reported to explain 79% of SNP heritability; using our improved heritability model, their estimated contribution is only 24%.
Wissenschaftlicher Artikel
Scientific Article
2015
Cai, N. ; Chang, S. ; Li, Y. ; Li, Q. ; Hu, J. ; Liang, J. ; Song, L. ; Kretzschmar, W. ; Gan, X. ; Nicod, J. ; Rivera, M. ; Deng, H. ; Du, B. ; Li, K. ; Sang, W. ; Gao, J. ; Gao, S. ; Ha, B. ; Ho, H.Y. ; Hu, C. ; Hu, Z. ; Huang, G. ; Jiang, G. ; Jiang, T. ; Jin, W. ; Li, G. ; Lin, Y.T. ; Liu, L. ; Liu, T. ; Liu, Y. ; Lu, Y. ; Lv, L. ; Meng, H. ; Qian, P. ; Sang, H. ; Shen, J. ; Shi, J. ; Sun, J. ; Tao, M. ; Wang, G. ; Wang, J. ; Wang, L. ; Wang, X. ; Yang, H. ; Yang, L. ; Yin, Y. ; Zhang, J. ; Zhang, K. ; Sun, N. ; Zhang, W. ; Zhang, X. ; Zhang, Z. ; Zhong, H. ; Breen, G. ; Marchini, J. ; Chen, Y. ; Xu, Q. ; Xu, X. ; Mott, R. ; Huang, G.J. ; Kendler, K. ; Flint, J.
Curr. Biol. 25, 1146-1156 (2015)
Adversity, particularly in early life, can cause illness. Clues to the responsible mechanisms may lie with the discovery of molecular signatures of stress, some of which include alterations to an individual's somatic genome. Here, using genome sequences from 11,670 women, we observed a highly significant association between a stress-related disease, major depression, and the amount of mtDNA (p = 9.00 × 10(-42), odds ratio 1.33 [95% confidence interval [CI] = 1.29-1.37]) and telomere length (p = 2.84 × 10(-14), odds ratio 0.85 [95% CI = 0.81-0.89]). While both telomere length and mtDNA amount were associated with adverse life events, conditional regression analyses showed the molecular changes were contingent on the depressed state. We tested this hypothesis with experiments in mice, demonstrating that stress causes both molecular changes, which are partly reversible and can be elicited by the administration of corticosterone. Together, these results demonstrate that changes in the amount of mtDNA and telomere length are consequences of stress and entering a depressed state. These findings identify increased amounts of mtDNA as a molecular marker of MD and have important implications for understanding how stress causes the disease.
Wissenschaftlicher Artikel
Scientific Article
CONVERGE consortium (Cai, N.)
Nature 523, 588-591 (2015)
Major depressive disorder (MDD), one of the most frequently encountered forms of mental illness and a leading cause of disability worldwide, poses a major challenge to genetic analysis. To date, no robustly replicated genetic loci have been identified, despite analysis of more than 9,000 cases. Here, using low-coverage whole-genome sequencing of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, we identified, and subsequently replicated in an independent sample, two loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene (P = 2.53 × 10(-10)), the other in an intron of the LHPP gene (P = 6.45 × 10(-12)). Analysis of 4,509 cases with a severe subtype of MDD, melancholia, yielded an increased genetic signal at the SIRT1 locus. We attribute our success to the recruitment of relatively homogeneous cases with severe illness.
Wissenschaftlicher Artikel
Scientific Article
Cai, N. ; Li, Y. ; Chang, S. ; Liang, J. ; Lin, C. ; Zhang, X. ; Liang, L. ; Hu, J. ; Chan, W. ; Kendler, K.S. ; Malinauskas, T. ; Huang, G.J. ; Li, Q. ; Mott, R. ; Flint, J.
Curr. Biol. 25, 3170-3177 (2015)
Control over the number of mtDNA molecules per cell appears to be tightly regulated, but the mechanisms involved are largely unknown. Reversible alterations in the amount of mtDNA occur in response to stress suggesting that control over the amount of mtDNA is involved in stress-related diseases including major depressive disorder (MDD). Using low-coverage sequence data from 10,442 Chinese women to compute the normalized numbers of reads mapping to the mitochondrial genome as a proxy for the amount of mtDNA, we identified two loci that contribute to mtDNA levels: one within the TFAM gene on chromosome 10 (rs11006126, p value = 8.73 × 10(-28), variance explained = 1.90%) and one over the CDK6 gene on chromosome 7 (rs445, p value = 6.03 × 10(-16), variance explained = 0.50%). Both loci replicated in an independent cohort. CDK6 is thus a new molecule involved in the control of mtDNA. We identify increased rates of heteroplasmy in women with MDD, and show from an experimental paradigm using mice that the increase is likely due to stress. Furthermore, at least one heteroplasmic variant is significantly associated with changes in the amount of mtDNA (position 513, p value = 3.27 × 10(-9), variance explained = 0.48%) suggesting site-specific heteroplasmy as a possible link between stress and increase in amount of mtDNA. These findings indicate the involvement of mitochondrial genome copy number and sequence in an organism's response to stress.
Wissenschaftlicher Artikel
Scientific Article