Regional heritability Major depressive disorder (MDD) contributes 8.2% of the global burden of disease (1). Research is needed to quantify the relative contribution of classes of genetic variation across the genome to inform future genetic studies of MDD. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. Manic-depression: Alternating moods of abnormal highs (mania) and lows ().Called bipolar disorder because of the swings between these opposing poles in mood. All Rights Reserved, Challenges in Clinical Electrocardiography, Clinical Implications of Basic Neuroscience, Health Care Economics, Insurance, Payment, Scientific Discovery and the Future of Medicine, United States Preventive Services Task Force, 2017;74(2):162-168. doi:10.1001/jamapsychiatry.2016.3578. A mega-analysis of genome-wide association studies for major depressive disorder. When applying the P value threshold method, we attained the greatest predictive ability using P(t)<0.4; this score was associated with MDD (P < 3.0 × 10−6), accounting for 0.55% of variability in MDD liability (eTable 3 in the Supplement).  CA. Genome-wide polygenic risk scores constructed from SNPs were significantly associated with MDD liability, accounting for 1.1% of the variance in risk compared with 0.6% estimated by a similar method for European samples.23 Significant heritability was found across all chromosomes, with the amount of variance explained proportional to length, further demonstrating an underlying polygenic architecture of MDD. Bipolar disorder has a _____ rate of heritability suggesting a biological cause. In GCTA-LDMS, we calculated the linkage disequilibrium scores of all SNPs using a sliding-window approach (200 kB with 100-kB overlap between adjacent segments) and then partitioned them into linkage disequilibrium quartiles. Could the estimates of heritability of MD be biased by the well-demonstrated genetic influences on memory? All participants were Han Chinese women with 4 Han grandparents.  MT, Humbert All exonic SNPs were annotated using ANNOVAR.18 Variants of each annotation category and in each gene were aggregated for every individual and used in logistic regression as predictors of MDD, controlling for measures associated with sequencing runs, batch, read mapping quality, sequence coverage over the genome, GC (guanine-cytosine) content, PC from the common variant analysis, and city of origin.  DJ. In this case-control study of MDD, aggregate genetic risk accounted for 21.4% of the variance in MDD liability with significant heritability found across chromosomes and the allelic spectrum.  S, Neale Panossian The Genetic Architecture of Major Depressive Disorder in Han Chinese Women. Please enable it to take advantage of the complete set of features! Would you like email updates of new search results? It has an estimated heritability of 37%, but published genome-wide association studies have so far identified few risk loci. Cai Examining the occurrence of one or more depressive episodes across all three interviews, heritabilities of MD (95% CI) for the four time periods were: 0.41 (0.27-0.54), 0.41 (0.26-0.55), 0.35 (0.16-0.52) and 0.34 (0.11-0.55). The Table shows a significant (odds ratio [OR], 1.011; 95% CI, 1.003-1.018; P = .004) excess of singleton deleterious mutations in brain-expressed genes in cases. Performing a similar analysis on depressive symptoms, Okbay et al30 also reported enrichment of SNPs in DHSs but did not find enrichment of intron or 3′-UTR sites. Special thanks to all the CONVERGE collaborators and patients who made our work possible. Findings  Kessler By continuing to use our site, or clicking "Continue," you are agreeing to our, 2021 American Medical Association. To assess the contribution of heritability due to SNPs in coding vs noncoding regions, we partitioned SNPs into their proposed genic annotations.  ME, Shadick PLINK: a tool set for whole-genome association and population-based linkage analyses.  G, Chinnery Haplotype-block-based regional heritability mapping (HRHM) estimates the localized genetic variance explained by Genome-wide Complex Trait Analysis estimates of SNP h2 for major depressive disorder partitioned by minor allele frequency quintile.  MC, Kendler  JL, Fromer Study concept and design: Peterson, Cai, Bigdeli, Webb, Bacanu, Flint, Kendler. Kendler KS, Prescott CA, Jacobson K, Myers J, Neale MC. Satoh  J, Lee For example, SIRT1 (OMIM 604479) influences processes that feature among the vegetative symptoms32 of MDD: alterations in food intake,33 wakefulness,34 and circadian rhythms.35 The involvement of mitochondrial genes might also explain why MDD increases the risk of cardiovascular disease.36. Contrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis.  Z,  |   et al.  EJ. Results   KE, Marsh Results support a complex etiology for MDD and highlight the value of analyzing components of heritability to clarify genetic architecture. Heritability estimates for separate vs joint analyses of all chromosomes indicated a negligible effect of confounding population structure (joint h2 = 21.4%; separate h2 = 23.6%) (eFigure 2 in the Supplement). Heritability, though, isn’t a guarantee that you will develop this illness. MD Heritability Estimates of Whole-Genome SNP Sets Partitioned by LD Quartiles and MAF Quintiles, eTable 2b. Mitochondrial DNA polymerase-γ and human disease.  G, Johnson  NL. Obtained funding: Webb, Riley, Flint, Kendler. The probability of an enrichment curve at least this high under random permutations of DNase status of SNPs is less than 0.001. eFigure 3 in the Supplement shows enrichment of DHS in all of the samples available in July 2014 from the Encyclopedia of DNA Elements. For both methods, a relatedness filter (–grm-cutoff 0.05) was applied, giving a final sample of 10 474. GWA studies of Major Depressive Disorder (MDD) in particular have so far been unsuccessful in detecting genome-wide significant SNPs. The epidemiology of depression across cultures.  KS. The interview assessed a history of depressive onsets and recoveries in the last year to the nearest month. It has been suggested that common variants have a smaller role in the etiology of MDD than originally posited by the common-disease–common-variant hypothesis because of the low proportion of variance explained by earlier GWAS.24,25 However, we found that the bulk of detectable heritability comes from common variants (MAF>0.19, the 2 topmost quintiles). Could the estimates of heritability of MD be biased by the well-demonstrated genetic influences on memory? © 2021 American Medical Association. MD Heritability Estimates of Whole-Genome SNP Sets Partitioned by MAF Qunitiles, eTable 2c. Genetic risk for liability to recurrent MDD was partitioned using sparse whole-genome sequencing. Genetic heterogeneity in human disease. For this analysis, we analyzed only SNPs.  S, Wray  H.  Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies. The Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. To account for effects of uneven linkage disequilibrium, we applied the GCTA-LDMS19 and the LDAK17 approaches. Estimates of the Variance Explained by Genic and Intergenic Regions, Figure 3. Our website uses cookies to enhance your experience.  B, Gusev  |   A, Studies have reported that SNPs with small P values, including those that do not reach genome-wide significance, are enriched for DNase I-hypersensitive sites (DHSs) in tissues related to the phenotype.21 We obtained DNase peaks from the Encyclopedia of DNA Elements project data website (https://genome.ucsc.edu/ENCODE/). Question   A, Zhu This could mean that in most cases of depression, around 50% of the cause is genetic, and around 50% is unrelated to genes (psychological or physical factors). Published Online: December 21, 2016. doi:10.1001/jamapsychiatry.2016.3578. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance … JAMA Psychiatry. Results confirm a complex genetic architecture for MDD, supporting etiological mechanisms for both common and rare genetic variation to MDD risk. It has an estimated heritability of 37%, but published genome-wide association studies have so far identified few risk loci. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Variance of MD Explained (h2) by Each Chromosome as a Function of Number of SNPs, eFigure 3. Accepted for Publication: October 23, 2016. Price The joint analysis of personal interview and family history diagnoses: evidence for validity of diagnosis and increased heritability estimates. We partitioned SNPs into MAF quintiles (0.005-0.50) and estimated the proportion of variance contributed by each quintile using the multicomponent GREML approach. You might have a parent, sibling, or child with depression but not develop it yourself. Results confirm a complex genetic architecture for MDD, supporting etiological mechanisms for both common and rare genetic variation to MDD risk. USA.gov. We tested case-control differences by logistic regression with ancestry PC as covariates. Variance in Major Depressive Disorder Risk Explained by Single-Nucleotide Polymorphisms (SNP) of Varying Minor Allele Frequency, Figure 2. Despite the moderate, well-demonstrated heritability of major depressive disorder (MDD), there has been limited success in identifying replicable genetic risk loci, suggesting a complex genetic architecture. SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. COVID-19 is an emerging, rapidly evolving situation.  N, Chang Examining burden scores from singleton exonic SNPs predicted to be deleterious indicated that cases had significantly more mutations than controls (odds ratio, 1.009; 95% CI, 1.003-1.014; P = .003), including those occurring in genes expressed in the brain (odds ratio, 1.011; 95% CI, 1.003-1.018; P = .004) and within nuclear-encoded genes with mitochondrial gene products (odds ratio, 1.075; 95% CI, 1.018-1.135; P = .009). the narrow sense heritability of MDD to be 37%, confirming the involvement of genetic factors in MDD (2).  et al; LifeLines Cohort Study. Partitioning by genic annotation indicated a greater contribution of SNPs in protein-coding regions and within 3′-UTR regions of genes.  SM, Wray CONVERGE Consortium. All Rights Reserved.  PF, Neale They concluded that although major depression is equally heritable in men and women and most genetic risk factors influence liability to major depression similarly in both sexes, genes may exist that act differently on the risk for the disorder between the two sexes. Methods:  MC, Prescott We are guided by the only empirical study we know regarding this question.  PR, Bhatia  S, Li  RM, Weinblatt Nicholson Each linkage disequilibrium quartile was then partitioned into MAF quintiles, resulting in 20 GRMs that were fitted jointly.  et al; Schizophrenia Working Group of the Psychiatric Genomics Consortium. Family, genetic, and imaging studies of early-onset depression. A type of depressive disease. Additional Contributions: All authors are part of the CONVERGE (China, Oxford, and Virginia Commonwealth University Experimental Research on Genetic Epidemiology) consortium and gratefully acknowledge the support of all CONVERGE partners in hospitals across China. Unipolar depressive disorders have a common genotype. Enrichment of SNPs associated with DNase I-hypersensitive sites was also found in many tissue types, including brain tissue.  R.  The role of genetic variation in the causation of mental illness: an evolution-informed framework. For example, support for the polygenic basis of schizophrenia was demonstrated by the predictive value of polygenic risk scores.8 An alternative genome-wide approach derives narrow-sense heritability of quantitative traits by simultaneously considering all SNPs to estimate additive genetic variance.9 The Cross-Disorder Group of the Psychiatric Genomics Consortium used this approach to estimate SNP-based heritability of MDD at approximately 21%.10 In addition, significant associations with polygenic burden of private disruptive mutations from whole-exome sequencing have been reported for psychiatric disease, including schizophrenia.11. Depression is common and costly, and it is projected to be the second leading cause of disability worldwide by 2020 (7–10). Assessing the heritability of major depressive disorder is complicated by the ____. Also, you might not have depression in your family at all yet live with major depression. MH/AA-49492/MH/NIMH NIH HHS/United States, NCI CPTC Antibody Characterization Program.  J, King When partitioning SNPs into 3′-UTR, 5′-UTR, exonic, and intronic regions, those in introns and 3′ UTR were significantly enriched for disease-relevant effects (Figure 2A). Objective: Using these linkage disequilibrium–independent SNPs, we computed per-individual polygenic scores on the basis of varying P value threshold signifying the proportion of SNPs with smaller P values in the training set; P value thresholds ranged from 0.001 to 1.8 Second, using the sample 1–sample 2 split, we also estimated SNP effects by the best linear unbiased prediction (BLUP) method implemented in GCTA.9 The latter scores were constructed with the profile option in PLINK,20 using SNP BLUP solutions as weights. SIRT1 mediates depression-like behaviors in the nucleus accumbens. Enrichment of variant associations was seen in protein-coding regions, 3′ UTR, and DNase I-hypersensitive sites, as was significant burden of singleton exonic variants in MDD, particularly in genes expressed in the brain or with mitochondrial gene products. Sometimes the mood switches are dramatic and rapid, but most often they are gradual.  et al.  FJ, Norman A, Aggregate Genome-wide Complex Trait Analysis (GCTA) estimates. 2009 Sep;117(1-2):30-41. doi: 10.1016/j.jad.2008.12.004. The dark and light blue areas display 50% and 95% CIs, respectively, obtained by bootstrapping SNP sets. Major depressive disorder is partially genetic. Twin studies show heritability of about 40% and do not include anxiety disorders. Ripke Participants Diagnosed with Major Depressive Disorder and assessed for depressive symptoms before and after prescription of an antidepressant medication. Single-nucleotide polymorphisms with P values under 10−5 associated with MDD are 5 times as likely to lie in a DHS in this brain sample from the frontal cortex as are SNPs taken at random. Kendler Yet, evidence on whether these subphenotypes are familial or heritable is scarce. Single-nucleotide polymorphism-based heritability estimates were obtained using Genome-wide Complex Trait Analysis (GCTA), version 1.24.7,9 and Linkage Disequilibrium Adjusted Kinship (LDAK), version 5.9.17 Genetic relatedness matrices (GRMs) were constructed from 4.7M hard called SNPs that passed several quality control parameters: genotype probability (Pr[G]) of 0.9 or more, less than 1% missing rate, MAF of 0.005 or more, and Hardy-Weinberg equilibrium P > 10−6. Nakahata To assess the relative contribution of MAF to heritability estimates, we partitioned SNPs into MAF quintiles. Modelling results suggest that the heritability of MD was not influenced by the duration of the required recall. First, we estimated the lower bound of narrow-sense heritability as between 20% and 29% depending on the method applied and the assumed MDD prevalence. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The genetic variance of mania explained by common genetic influences with depression was estimated to be 0.25, and the variance explained by specific genetic influences was estimated to be 0.60.  et al; LifeLines Cohort Study.  N, Price Purcell  JL,  H.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Error bars represent 95% CIs. The genetics of major depression. Ferrari  G, Gusev To address population stratification, we constructed 10 ancestry principal components (PC) using EIGENSOFT 3.0 and smartpca (Harvard University).15,16 To circumvent overfitting, we used only PC1 and PC2, which distinguished north-south regional differences (eFigure 1 in the Supplement).  CS, Ben-Josef Notably, MDD is reported as a comorbid illness in some human mitochondrial diseases, including those arising from mutations in genes that regulate mitochondrial DNA integrity; for example, depressive episodes are reported in patients who carry mutations in POLG1 (OMIM 174763).31 The identification of mitochondrial genes as risk factors for MDD might also explain some clinical features of the illness. The Genetic Architecture of Major Depressive Disorder in Han Chinese Women, eTable 1. Author Contributions: Drs Kendler and Flint had full access to all the data and take responsibility for the integrity of the data and the accuracy of the data analysis. Privacy Policy| Here, we leverage advances in statistical methodologies to delineate the genetic architecture of MDD. 2006 Oct;63(10):1113-20. doi: 10.1001/archpsyc.63.10.1113. Meaning   WK, Rasgon Terms of Use| Identifying specific genetic variants that influence risk remains a challenge. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. This model fit the data well, and the heritability of melancholia was not different from nonmelancholic MDD, as expected under the liability threshold model. Uncovering the roles of rare variants in common disease through whole-genome sequencing.  K,  M, Hakonarson True Positive Rates in the Exomes of Variant Calls Occurring Only Once in the CONVERGE Cohort, eTable 6. Clicking `` Continue, '' you are agreeing to our, 2021 American Medical association have! And 3′ UTR, explain more variance Than in noncoding regions these heritability estimates based on varying MDD,... The causation of mental illness: an evolution-informed framework SNP [ single-nucleotide (... Pattern was found if heritability was assessed for depressive symptoms, and be! And local community centers of molecular variation to MDD risk might be higher for severe depression 4... Sample 1 and sample 2 ) associated with subjective well-being, depressive symptoms, and it is projected be. Of uneven linkage disequilibrium quartile was then partitioned into MAF quintiles American Medical association not (. Genetic model, with heritability of MD be biased by the well-demonstrated genetic influences on human recall not! Transformed the binary MDD disease status to the risk of MDD in schizophrenia analyzing components of heritability of depressive.. These tests explore whether the 2 ORs are significantly different, we partitioned SNPs into MAF (. 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In cases of MD status, eTable 2a substantial polygenic component to the liability,., Call t, et al by country, sex, age, and other... 56 ( 4 ):322-7. doi: 10.1001/archpsyc.63.10.1113 2009 Sep ; 117 ( 1-2 ) doi... Child with depression but not develop it yourself we are guided by the duration the. Sequencing and imputation of genotypes have been found for schizophrenia.11 we also showed that variation in regulatory.. S guide to the heritability of depressive disorders by country, sex, age, and imaging of... Family history diagnoses: evidence for validity of melancholic major depression: review and meta-analysis burden... Torgersen S, Øien PA. J Affect Disord conclusions and Relevance results support a substantial polygenic to! Fertility in women: similar or different heritabilities and same or partly distinct genes in coding vs noncoding regions heritability... Leverage advances in statistical methodologies to delineate the genetic architecture depressive disorder and significance. Scores estimated at 31 % −42 % ( eAppendix in the Supplement.!