Browsing by Subject "Genetic Loci"

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    ItemOpen Access
    A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese.
    (PLoS Genet, 2010-02-19) Tsai, Fuu-Jen; Yang, Chi-Fan; Chen, Ching-Chu; Chuang, Lee-Ming; Lu, Chieh-Hsiang; Chang, Chwen-Tzuei; Wang, Tzu-Yuan; Chen, Rong-Hsing; Shiu, Chiung-Fang; Liu, Yi-Min; Chang, Chih-Chun; Chen, Pei; Chen, Chien-Hsiun; Fann, Cathy SJ; Chen, Yuan-Tsong; Wu, Jer-Yuarn
    To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54x10(-10); odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36-1.82), and serine racemase (SRR) (P = 3.06x10(-9); OR = 1.28; 95% CI = 1.18-1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65x10(-10); OR = 1.29, 95% CI = 1.19-1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations.
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    ItemOpen Access
    CASP7 variants modify susceptibility to cervical cancer in Chinese women.
    (Scientific reports, 2015-01) Shi, Ting-Yan; He, Jing; Wang, Meng-Yun; Zhu, Mei-Ling; Yu, Ke-Da; Shao, Zhi-Ming; Sun, Meng-Hong; Wu, Xiaohua; Cheng, Xi; Wei, Qingyi
    Polymorphisms in Caspase-7 (CASP7) may modulate the programmed cell death and thus contribute to cervical cancer risk. In this case-control study of 1,486 cervical cancer cases and 1,301 controls, we investigated associations between four potentially functional polymorphisms in CASP7 and cervical cancer risk and evaluated their locus-locus interaction effects on the risk. The genotype-phenotype correlation was performed by a generalized linear regression model. We found that the rs4353229 polymorphism was associated with cervical cancer risk (under a recessive model: crude OR = 1.20, 95% CI = 1.02-1.40). Compared with the TT genotype, the rs10787498GT genotype was associated with an increased cervical cancer risk (adjusted OR = 1.19, 95% CI = 1.00-1.41). Combination analysis showed that subjects with four putative risk genotypes had a 1.54-fold increased cancer risk, compared with those who carried three or less putative risk genotypes. We also observed significant locus-locus joint effects on the risk, which may be mediated by the polymorphisms regulating CASP7 mRNA expression. Subsequent multifactor dimensionality reduction and classification and regression tree analyses indicated that the CASP7 genotypes might have a locus-locus interaction effect that modulated cervical cancer risk. Out data suggest that CASP7 polymorphisms may interact to modify cervical cancer risk by a possible mechanism of regulating CASP7 mRNA expression.
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    ItemOpen Access
    Characterization of the standard and recommended CODIS markers.
    (Journal of forensic sciences, 2013-01) Katsanis, Sara H; Wagner, Jennifer K
    As U.S. courts grapple with constitutional challenges to DNA identification applications, judges are resting legal decisions on the fingerprint analogy, questioning whether the information from a DNA profile could, in light of scientific advances, reveal biomedically relevant information. While CODIS loci were selected largely because they lack phenotypic associations, how this criterion was assessed is unclear. To clarify their phenotypic relevance, we describe the standard and recommended CODIS markers within the context of what is known currently about the genome. We characterize the genomic regions and phenotypic associations of the 24 standard and suggested CODIS markers. None of the markers are within exons, although 12 are intragenic. No CODIS genotypes are associated with known phenotypes. This study provides clarification of the genomic significance of the key identification markers and supports--independent of the forensic scientific community--that the CODIS profiles provide identification but not sensitive or biomedically relevant information.
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    ItemOpen Access
    Depression in pregnancy, infant birth weight and DNA methylation of imprint regulatory elements.
    (Epigenetics : official journal of the DNA Methylation Society, 2012-07) Liu, Y; Murphy, SK; Murtha, AP; Fuemmeler, BF; Schildkraut, J; Huang, Z; Overcash, F; Kurtzberg, J; Jirtle, R; Iversen, ES; Forman, MR; Hoyo, C
    Depressed mood in pregnancy has been linked to low birth weight (LBW, 4,500 g) infants had 5.9% higher methylation at the PLAGL1 DMR compared with normal birth weight infants. Our findings confirm that severe maternal depressed mood in pregnancy is associated with LBW, and that MEG3 and IGF2 plasticity may play important roles.
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    ItemRestricted
    Evolution of the sex-related locus and genomic features shared in microsporidia and fungi.
    (PLoS One, 2010-05-07) Lee, Soo Chan; Corradi, Nicolas; Doan, Sylvia; Dietrich, Fred S; Keeling, Patrick J; Heitman, Joseph
    BACKGROUND: Microsporidia are obligate intracellular, eukaryotic pathogens that infect a wide range of animals from nematodes to humans, and in some cases, protists. The preponderance of evidence as to the origin of the microsporidia reveals a close relationship with the fungi, either within the kingdom or as a sister group to it. Recent phylogenetic studies and gene order analysis suggest that microsporidia share a particularly close evolutionary relationship with the zygomycetes. METHODOLOGY/PRINCIPAL FINDINGS: Here we expanded this analysis and also examined a putative sex-locus for variability between microsporidian populations. Whole genome inspection reveals a unique syntenic gene pair (RPS9-RPL21) present in the vast majority of fungi and the microsporidians but not in other eukaryotic lineages. Two other unique gene fusions (glutamyl-prolyl tRNA synthetase and ubiquitin-ribosomal subunit S30) that are present in metazoans, choanoflagellates, and filasterean opisthokonts are unfused in the fungi and microsporidians. One locus previously found to be conserved in many microsporidian genomes is similar to the sex locus of zygomycetes in gene order and architecture. Both sex-related and sex loci harbor TPT, HMG, and RNA helicase genes forming a syntenic gene cluster. We sequenced and analyzed the sex-related locus in 11 different Encephalitozoon cuniculi isolates and the sibling species E. intestinalis (3 isolates) and E. hellem (1 isolate). There was no evidence for an idiomorphic sex-related locus in this Encephalitozoon species sample. According to sequence-based phylogenetic analyses, the TPT and RNA helicase genes flanking the HMG genes are paralogous rather than orthologous between zygomycetes and microsporidians. CONCLUSION/SIGNIFICANCE: The unique genomic hallmarks between microsporidia and fungi are independent of sequence based phylogenetic comparisons and further contribute to define the borders of the fungal kingdom and support the classification of microsporidia as unusual derived fungi. And the sex/sex-related loci appear to have been subject to frequent gene conversion and translocations in microsporidia and zygomycetes.
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    ItemOpen Access
    Functional annotation signatures of disease susceptibility loci improve SNP association analysis.
    (BMC Genomics, 2014-05-24) Iversen, ES; Lipton, G; Clyde, MA; Monteiro, ANA
    BACKGROUND: Genetic association studies are conducted to discover genetic loci that contribute to an inherited trait, identify the variants behind these associations and ascertain their functional role in determining the phenotype. To date, functional annotations of the genetic variants have rarely played more than an indirect role in assessing evidence for association. Here, we demonstrate how these data can be systematically integrated into an association study's analysis plan. RESULTS: We developed a Bayesian statistical model for the prior probability of phenotype-genotype association that incorporates data from past association studies and publicly available functional annotation data regarding the susceptibility variants under study. The model takes the form of a binary regression of association status on a set of annotation variables whose coefficients were estimated through an analysis of associated SNPs in the GWAS Catalog (GC). The functional predictors examined included measures that have been demonstrated to correlate with the association status of SNPs in the GC and some whose utility in this regard is speculative: summaries of the UCSC Human Genome Browser ENCODE super-track data, dbSNP function class, sequence conservation summaries, proximity to genomic variants in the Database of Genomic Variants and known regulatory elements in the Open Regulatory Annotation database, PolyPhen-2 probabilities and RegulomeDB categories. Because we expected that only a fraction of the annotations would contribute to predicting association, we employed a penalized likelihood method to reduce the impact of non-informative predictors and evaluated the model's ability to predict GC SNPs not used to construct the model. We show that the functional data alone are predictive of a SNP's presence in the GC. Further, using data from a genome-wide study of ovarian cancer, we demonstrate that their use as prior data when testing for association is practical at the genome-wide scale and improves power to detect associations. CONCLUSIONS: We show how diverse functional annotations can be efficiently combined to create 'functional signatures' that predict the a priori odds of a variant's association to a trait and how these signatures can be integrated into a standard genome-wide-scale association analysis, resulting in improved power to detect truly associated variants.
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    ItemOpen Access
    Genetic diversity fuels gene discovery for tobacco and alcohol use.
    (Nature, 2022-12) Saunders, Gretchen RB; Wang, Xingyan; Chen, Fang; Jang, Seon-Kyeong; Liu, Mengzhen; Wang, Chen; Gao, Shuang; Jiang, Yu; Khunsriraksakul, Chachrit; Otto, Jacqueline M; Addison, Clifton; Akiyama, Masato; Albert, Christine M; Aliev, Fazil; Alonso, Alvaro; Arnett, Donna K; Ashley-Koch, Allison E; Ashrani, Aneel A; Barnes, Kathleen C; Barr, R Graham; Bartz, Traci M; Becker, Diane M; Bielak, Lawrence F; Benjamin, Emelia J; Bis, Joshua C; Bjornsdottir, Gyda; Blangero, John; Bleecker, Eugene R; Boardman, Jason D; Boerwinkle, Eric; Boomsma, Dorret I; Boorgula, Meher Preethi; Bowden, Donald W; Brody, Jennifer A; Cade, Brian E; Chasman, Daniel I; Chavan, Sameer; Chen, Yii-Der Ida; Chen, Zhengming; Cheng, Iona; Cho, Michael H; Choquet, Hélène; Cole, John W; Cornelis, Marilyn C; Cucca, Francesco; Curran, Joanne E; de Andrade, Mariza; Dick, Danielle M; Docherty, Anna R; Duggirala, Ravindranath; Eaton, Charles B; Ehringer, Marissa A; Esko, Tõnu; Faul, Jessica D; Fernandes Silva, Lilian; Fiorillo, Edoardo; Fornage, Myriam; Freedman, Barry I; Gabrielsen, Maiken E; Garrett, Melanie E; Gharib, Sina A; Gieger, Christian; Gillespie, Nathan; Glahn, David C; Gordon, Scott D; Gu, Charles C; Gu, Dongfeng; Gudbjartsson, Daniel F; Guo, Xiuqing; Haessler, Jeffrey; Hall, Michael E; Haller, Toomas; Harris, Kathleen Mullan; He, Jiang; Herd, Pamela; Hewitt, John K; Hickie, Ian; Hidalgo, Bertha; Hokanson, John E; Hopfer, Christian; Hottenga, JoukeJan; Hou, Lifang; Huang, Hongyan; Hung, Yi-Jen; Hunter, David J; Hveem, Kristian; Hwang, Shih-Jen; Hwu, Chii-Min; Iacono, William; Irvin, Marguerite R; Jee, Yon Ho; Johnson, Eric O; Joo, Yoonjung Y; Jorgenson, Eric; Justice, Anne E; Kamatani, Yoichiro; Kaplan, Robert C; Kaprio, Jaakko; Kardia, Sharon LR; Keller, Matthew C; Kelly, Tanika N; Kooperberg, Charles; Korhonen, Tellervo; Kraft, Peter; Krauter, Kenneth; Kuusisto, Johanna; Laakso, Markku; Lasky-Su, Jessica; Lee, Wen-Jane; Lee, James J; Levy, Daniel; Li, Liming; Li, Kevin; Li, Yuqing; Lin, Kuang; Lind, Penelope A; Liu, Chunyu; Lloyd-Jones, Donald M; Lutz, Sharon M; Ma, Jiantao; Mägi, Reedik; Manichaikul, Ani; Martin, Nicholas G; Mathur, Ravi; Matoba, Nana; McArdle, Patrick F; McGue, Matt; McQueen, Matthew B; Medland, Sarah E; Metspalu, Andres; Meyers, Deborah A; Millwood, Iona Y; Mitchell, Braxton D; Mohlke, Karen L; Moll, Matthew; Montasser, May E; Morrison, Alanna C; Mulas, Antonella; Nielsen, Jonas B; North, Kari E; Oelsner, Elizabeth C; Okada, Yukinori; Orrù, Valeria; Palmer, Nicholette D; Palviainen, Teemu; Pandit, Anita; Park, S Lani; Peters, Ulrike; Peters, Annette; Peyser, Patricia A; Polderman, Tinca JC; Rafaels, Nicholas; Redline, Susan; Reed, Robert M; Reiner, Alex P; Rice, John P; Rich, Stephen S; Richmond, Nicole E; Roan, Carol; Rotter, Jerome I; Rueschman, Michael N; Runarsdottir, Valgerdur; Saccone, Nancy L; Schwartz, David A; Shadyab, Aladdin H; Shi, Jingchunzi; Shringarpure, Suyash S; Sicinski, Kamil; Skogholt, Anne Heidi; Smith, Jennifer A; Smith, Nicholas L; Sotoodehnia, Nona; Stallings, Michael C; Stefansson, Hreinn; Stefansson, Kari; Stitzel, Jerry A; Sun, Xiao; Syed, Moin; Tal-Singer, Ruth; Taylor, Amy E; Taylor, Kent D; Telen, Marilyn J; Thai, Khanh K; Tiwari, Hemant; Turman, Constance; Tyrfingsson, Thorarinn; Wall, Tamara L; Walters, Robin G; Weir, David R; Weiss, Scott T; White, Wendy B; Whitfield, John B; Wiggins, Kerri L; Willemsen, Gonneke; Willer, Cristen J; Winsvold, Bendik S; Xu, Huichun; Yanek, Lisa R; Yin, Jie; Young, Kristin L; Young, Kendra A; Yu, Bing; Zhao, Wei; Zhou, Wei; Zöllner, Sebastian; Zuccolo, Luisa; 23andMe Research Team; Biobank Japan Project; Batini, Chiara; Bergen, Andrew W; Bierut, Laura J; David, Sean P; Gagliano Taliun, Sarah A; Hancock, Dana B; Jiang, Bibo; Munafò, Marcus R; Thorgeirsson, Thorgeir E; Liu, Dajiang J; Vrieze, Scott
    Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1-4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.
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    ItemOpen Access
    Genome-wide association study of acute kidney injury after coronary bypass graft surgery identifies susceptibility loci.
    (Kidney Int, 2015-10) Stafford-Smith, Mark; Li, Yi-Ju; Mathew, Joseph P; Li, Yen-Wei; Ji, Yunqi; Phillips-Bute, Barbara G; Milano, Carmelo A; Newman, Mark F; Kraus, William E; Kertai, Miklos D; Shah, Svati H; Podgoreanu, Mihai V; Duke Perioperative Genetics and Safety Outcomes (PEGASUS) Investigative Team
    Acute kidney injury (AKI) is a common, serious complication of cardiac surgery. Since prior studies have supported a genetic basis for postoperative AKI, we conducted a genome-wide association study (GWAS) for AKI following coronary bypass graft (CABG) surgery. The discovery data set consisted of 873 nonemergent CABG surgery patients with cardiopulmonary bypass (PEGASUS), while a replication data set had 380 cardiac surgical patients (CATHGEN). Single-nucleotide polymorphism (SNP) data were based on Illumina Human610-Quad (PEGASUS) and OMNI1-Quad (CATHGEN) BeadChips. We used linear regression with adjustment for a clinical AKI risk score to test SNP associations with the postoperative peak rise relative to preoperative serum creatinine concentration as a quantitative AKI trait. Nine SNPs meeting significance in the discovery set were detected. The rs13317787 in GRM7|LMCD1-AS1 intergenic region (3p21.6) and rs10262995 in BBS9 (7p14.3) were replicated with significance in the CATHGEN data set and exhibited significantly strong overall association following meta-analysis. Additional fine mapping using imputed SNPs across these two regions and meta-analysis found genome-wide significance at the GRM7|LMCD1-AS1 locus and a significantly strong association at BBS9. Thus, through an unbiased GWAS approach, we found two new loci associated with post-CABG AKI providing new insights into the pathogenesis of perioperative AKI.
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    Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study.
    (Aging Cell, 2013-04) Beekman, Marian; Blanché, Hélène; Perola, Markus; Hervonen, Anti; Bezrukov, Vladyslav; Sikora, Ewa; Flachsbart, Friederike; Christiansen, Lene; De Craen, Anton JM; Kirkwood, Tom BL; Rea, Irene Maeve; Poulain, Michel; Robine, Jean-Marie; Valensin, Silvana; Stazi, Maria Antonietta; Passarino, Giuseppe; Deiana, Luca; Gonos, Efstathios S; Paternoster, Lavinia; Sørensen, Thorkild IA; Tan, Qihua; Helmer, Quinta; van den Akker, Erik B; Deelen, Joris; Martella, Francesca; Cordell, Heather J; Ayers, Kristin L; Vaupel, James W; Törnwall, Outi; Johnson, Thomas E; Schreiber, Stefan; Lathrop, Mark; Skytthe, Axel; Westendorp, Rudi GJ; Christensen, Kaare; Gampe, Jutta; Nebel, Almut; Houwing-Duistermaat, Jeanine J; Slagboom, Pieternella Eline; Franceschi, Claudio; GEHA consortium
    Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.
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    GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
    (The American journal of psychiatry, 2023-10) Docherty, Anna R; Mullins, Niamh; Ashley-Koch, Allison E; Qin, Xuejun; Coleman, Jonathan RI; Shabalin, Andrey; Kang, JooEun; Murnyak, Balasz; Wendt, Frank; Adams, Mark; Campos, Adrian I; DiBlasi, Emily; Fullerton, Janice M; Kranzler, Henry R; Bakian, Amanda V; Monson, Eric T; Rentería, Miguel E; Walss-Bass, Consuelo; Andreassen, Ole A; Behera, Chittaranjan; Bulik, Cynthia M; Edenberg, Howard J; Kessler, Ronald C; Mann, J John; Nurnberger, John I; Pistis, Giorgio; Streit, Fabian; Ursano, Robert J; Polimanti, Renato; Dennis, Michelle; Garrett, Melanie; Hair, Lauren; Harvey, Philip; Hauser, Elizabeth R; Hauser, Michael A; Huffman, Jennifer; Jacobson, Daniel; Madduri, Ravi; McMahon, Benjamin; Oslin, David W; Trafton, Jodie; Awasthi, Swapnil; Berrettini, Wade H; Bohus, Martin; Chang, Xiao; Chen, Hsi-Chung; Chen, Wei J; Christensen, Erik D; Crow, Scott; Duriez, Philibert; Edwards, Alexis C; Fernández-Aranda, Fernando; Galfalvy, Hanga; Gandal, Michael; Gorwood, Philip; Guo, Yiran; Hafferty, Jonathan D; Hakonarson, Hakon; Halmi, Katherine A; Hishimoto, Akitoyo; Jain, Sonia; Jamain, Stéphane; Jiménez-Murcia, Susana; Johnson, Craig; Kaplan, Allan S; Kaye, Walter H; Keel, Pamela K; Kennedy, James L; Kim, Minsoo; Klump, Kelly L; Levey, Daniel F; Li, Dong; Liao, Shih-Cheng; Lieb, Klaus; Lilenfeld, Lisa; Marshall, Christian R; Mitchell, James E; Okazaki, Satoshi; Otsuka, Ikuo; Pinto, Dalila; Powers, Abigail; Ramoz, Nicolas; Ripke, Stephan; Roepke, Stefan; Rozanov, Vsevolod; Scherer, Stephen W; Schmahl, Christian; Sokolowski, Marcus; Starnawska, Anna; Strober, Michael; Su, Mei-Hsin; Thornton, Laura M; Treasure, Janet; Ware, Erin B; Watson, Hunna J; Witt, Stephanie H; Woodside, D Blake; Yilmaz, Zeynep; Zillich, Lea; Adolfsson, Rolf; Agartz, Ingrid; Alda, Martin; Alfredsson, Lars; Appadurai, Vivek; Artigas, María Soler; Van der Auwera, Sandra; Azevedo, M Helena; Bass, Nicholas; Bau, Claiton HD; Baune, Bernhard T; Bellivier, Frank; Berger, Klaus; Biernacka, Joanna M; Bigdeli, Tim B; Binder, Elisabeth B; Boehnke, Michael; Boks, Marco P; Braff, David L; Bryant, Richard; Budde, Monika; Byrne, Enda M; Cahn, Wiepke; Castelao, Enrique; Cervilla, Jorge A; Chaumette, Boris; Corvin, Aiden; Craddock, Nicholas; Djurovic, Srdjan; Foo, Jerome C; Forstner, Andreas J; Frye, Mark; Gatt, Justine M; Giegling, Ina; Grabe, Hans J; Green, Melissa J; Grevet, Eugenio H; Grigoroiu-Serbanescu, Maria; Gutierrez, Blanca; Guzman-Parra, Jose; Hamshere, Marian L; Hartmann, Annette M; Hauser, Joanna; Heilmann-Heimbach, Stefanie; Hoffmann, Per; Ising, Marcus; Jones, Ian; Jones, Lisa A; Jonsson, Lina; Kahn, René S; Kelsoe, John R; Kendler, Kenneth S; Kloiber, Stefan; Koenen, Karestan C; Kogevinas, Manolis; Krebs, Marie-Odile; Landén, Mikael; Leboyer, Marion; Lee, Phil H; Levinson, Douglas F; Liao, Calwing; Lissowska, Jolanta; Mayoral, Fermin; McElroy, Susan L; McGrath, Patrick; McGuffin, Peter; McQuillin, Andrew; Mehta, Divya; Melle, Ingrid; Mitchell, Philip B; Molina, Esther; Morken, Gunnar; Nievergelt, Caroline; Nöthen, Markus M; O'Donovan, Michael C; Ophoff, Roel A; Owen, Michael J; Pato, Carlos; Pato, Michele T; Penninx, Brenda WJH; Potash, James B; Power, Robert A; Preisig, Martin; Quested, Digby; Ramos-Quiroga, Josep Antoni; Reif, Andreas; Ribasés, Marta; Richarte, Vanesa; Rietschel, Marcella; Rivera, Margarita; Roberts, Andrea; Roberts, Gloria; Rouleau, Guy A; Rovaris, Diego L; Sanders, Alan R; Schofield, Peter R; Schulze, Thomas G; Scott, Laura J; Serretti, Alessandro; Shi, Jianxin; Sirignano, Lea; Sklar, Pamela; Smeland, Olav B; Smoller, Jordan W; Sonuga-Barke, Edmund JS; Trzaskowski, Maciej; Tsuang, Ming T; Turecki, Gustavo; Vilar-Ribó, Laura; Vincent, John B; Völzke, Henry; Walters, James TR; Weickert, Cynthia Shannon; Weickert, Thomas W; Weissman, Myrna M; Williams, Leanne M; Wray, Naomi R; Zai, Clement C; Agerbo, Esben; Børglum, Anders D; Breen, Gerome; Demontis, Ditte; Erlangsen, Annette; Gelernter, Joel; Glatt, Stephen J; Hougaard, David M; Hwu, Hai-Gwo; Kuo, Po-Hsiu; Lewis, Cathryn M; Li, Qingqin S; Liu, Chih-Min; Martin, Nicholas G; McIntosh, Andrew M; Medland, Sarah E; Mors, Ole; Nordentoft, Merete; Olsen, Catherine M; Porteous, David; Smith, Daniel J; Stahl, Eli A; Stein, Murray B; Wasserman, Danuta; Werge, Thomas; Whiteman, David C; Willour, Virginia; VA Million Veteran Program (MVP); MVP Suicide Exemplar Workgroup; Suicide Working Group of the Psychiatric Genomics Consortium; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Eating Disorder Working Group of the Psychiatric Genomics Consortium; German Borderline Genomics Consortium; Coon, Hilary; Beckham, Jean C; Kimbrel, Nathan A; Ruderfer, Douglas M

    Objective

    Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.

    Methods

    This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.

    Results

    Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.

    Conclusions

    This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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    ItemOpen Access
    International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.
    (Nature communications, 2019-10) Nievergelt, Caroline M; Maihofer, Adam X; Klengel, Torsten; Atkinson, Elizabeth G; Chen, Chia-Yen; Choi, Karmel W; Coleman, Jonathan RI; Dalvie, Shareefa; Duncan, Laramie E; Gelernter, Joel; Levey, Daniel F; Logue, Mark W; Polimanti, Renato; Provost, Allison C; Ratanatharathorn, Andrew; Stein, Murray B; Torres, Katy; Aiello, Allison E; Almli, Lynn M; Amstadter, Ananda B; Andersen, Søren B; Andreassen, Ole A; Arbisi, Paul A; Ashley-Koch, Allison E; Austin, S Bryn; Avdibegovic, Esmina; Babić, Dragan; Bækvad-Hansen, Marie; Baker, Dewleen G; Beckham, Jean C; Bierut, Laura J; Bisson, Jonathan I; Boks, Marco P; Bolger, Elizabeth A; Børglum, Anders D; Bradley, Bekh; Brashear, Megan; Breen, Gerome; Bryant, Richard A; Bustamante, Angela C; Bybjerg-Grauholm, Jonas; Calabrese, Joseph R; Caldas-de-Almeida, José M; Dale, Anders M; Daly, Mark J; Daskalakis, Nikolaos P; Deckert, Jürgen; Delahanty, Douglas L; Dennis, Michelle F; Disner, Seth G; Domschke, Katharina; Dzubur-Kulenovic, Alma; Erbes, Christopher R; Evans, Alexandra; Farrer, Lindsay A; Feeny, Norah C; Flory, Janine D; Forbes, David; Franz, Carol E; Galea, Sandro; Garrett, Melanie E; Gelaye, Bizu; Geuze, Elbert; Gillespie, Charles; Uka, Aferdita Goci; Gordon, Scott D; Guffanti, Guia; Hammamieh, Rasha; Harnal, Supriya; Hauser, Michael A; Heath, Andrew C; Hemmings, Sian MJ; Hougaard, David Michael; Jakovljevic, Miro; Jett, Marti; Johnson, Eric Otto; Jones, Ian; Jovanovic, Tanja; Qin, Xue-Jun; Junglen, Angela G; Karstoft, Karen-Inge; Kaufman, Milissa L; Kessler, Ronald C; Khan, Alaptagin; Kimbrel, Nathan A; King, Anthony P; Koen, Nastassja; Kranzler, Henry R; Kremen, William S; Lawford, Bruce R; Lebois, Lauren AM; Lewis, Catrin E; Linnstaedt, Sarah D; Lori, Adriana; Lugonja, Bozo; Luykx, Jurjen J; Lyons, Michael J; Maples-Keller, Jessica; Marmar, Charles; Martin, Alicia R; Martin, Nicholas G; Maurer, Douglas; Mavissakalian, Matig R; McFarlane, Alexander; McGlinchey, Regina E; McLaughlin, Katie A; McLean, Samuel A; McLeay, Sarah; Mehta, Divya; Milberg, William P; Miller, Mark W; Morey, Rajendra A; Morris, Charles Phillip; Mors, Ole; Mortensen, Preben B; Neale, Benjamin M; Nelson, Elliot C; Nordentoft, Merete; Norman, Sonya B; O'Donnell, Meaghan; Orcutt, Holly K; Panizzon, Matthew S; Peters, Edward S; Peterson, Alan L; Peverill, Matthew; Pietrzak, Robert H; Polusny, Melissa A; Rice, John P; Ripke, Stephan; Risbrough, Victoria B; Roberts, Andrea L; Rothbaum, Alex O; Rothbaum, Barbara O; Roy-Byrne, Peter; Ruggiero, Ken; Rung, Ariane; Rutten, Bart PF; Saccone, Nancy L; Sanchez, Sixto E; Schijven, Dick; Seedat, Soraya; Seligowski, Antonia V; Seng, Julia S; Sheerin, Christina M; Silove, Derrick; Smith, Alicia K; Smoller, Jordan W; Sponheim, Scott R; Stein, Dan J; Stevens, Jennifer S; Sumner, Jennifer A; Teicher, Martin H; Thompson, Wesley K; Trapido, Edward; Uddin, Monica; Ursano, Robert J; van den Heuvel, Leigh Luella; Van Hooff, Miranda; Vermetten, Eric; Vinkers, Christiaan H; Voisey, Joanne; Wang, Yunpeng; Wang, Zhewu; Werge, Thomas; Williams, Michelle A; Williamson, Douglas E; Winternitz, Sherry; Wolf, Christiane; Wolf, Erika J; Wolff, Jonathan D; Yehuda, Rachel; Young, Ross McD; Young, Keith A; Zhao, Hongyu; Zoellner, Lori A; Liberzon, Israel; Ressler, Kerry J; Haas, Magali; Koenen, Karestan C
    The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.
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    Mutation accumulation may be a minor force in shaping life history traits.
    (PLoS One, 2012) Dańko, Maciej Jan; Kozłowski, Jan; Vaupel, James Walton; Baudisch, Annette
    Is senescence the adaptive result of tradeoffs between younger and older ages or the nonadaptive burden of deleterious mutations that act at older ages? To shed new light on this unresolved question we combine adaptive and nonadaptive processes in a single model. Our model uses Penna's bit-strings to capture different age-specific mutational patterns. Each pattern represents a genotype and for each genotype we find the life history strategy that maximizes fitness. Genotypes compete with each other and are subject to selection and to new mutations over generations until equilibrium in gene-frequencies is reached. The mutation-selection equilibrium provides information about mutational load and the differential effects of mutations on a life history trait--the optimal age at maturity. We find that mutations accumulate only at ages with negligible impact on fitness and that mutation accumulation has very little effect on the optimal age at maturity. These results suggest that life histories are largely determined by adaptive processes. The non-adaptive process of mutation accumulation seems to be unimportant at evolutionarily relevant ages.
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    Novel loci and pathways significantly associated with longevity.
    (Sci Rep, 2016-02-25) Zeng, Yi; Nie, Chao; Min, Junxia; Liu, Xiaomin; Li, Mengmeng; Chen, Huashuai; Xu, Hanshi; Wang, Mingbang; Ni, Ting; Li, Yang; Yan, Han; Zhang, Jin-Pei; Song, Chun; Chi, Li-Qing; Wang, Han-Ming; Dong, Jie; Zheng, Gu-Yan; Lin, Li; Qian, Feng; Qi, Yanwei; Liu, Xiao; Cao, Hongzhi; Wang, Yinghao; Zhang, Lijuan; Li, Zhaochun; Zhou, Yufeng; Wang, Yan; Lu, Jiehua; Li, Jianxin; Qi, Ming; Bolund, Lars; Yashin, Anatoliy; Land, Kenneth C; Gregory, Simon; Yang, Ze; Gottschalk, William; Tao, Wei; Wang, Jian; Wang, Jun; Xu, Xun; Bae, Harold; Nygaard, Marianne; Christiansen, Lene; Christensen, Kaare; Franceschi, Claudio; Lutz, Michael W; Gu, Jun; Tan, Qihua; Perls, Thomas; Sebastiani, Paola; Deelen, Joris; Slagboom, Eline; Hauser, Elizabeth; Xu, Huji; Tian, Xiao-Li; Yang, Huanming; Vaupel, James W
    Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10(-5)). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.
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    rbcL and matK earn two thumbs up as the core DNA barcode for ferns.
    (PloS one, 2011-01) Li, F; Kuo, L; Rothfels, CJ; Ebihara, A; Chiou, W; Windham, MD; Pryer, KM
    BACKGROUND: DNA barcoding will revolutionize our understanding of fern ecology, most especially because the accurate identification of the independent but cryptic gametophyte phase of the fern's life history--an endeavor previously impossible--will finally be feasible. In this study, we assess the discriminatory power of the core plant DNA barcode (rbcL and matK), as well as alternatively proposed fern barcodes (trnH-psbA and trnL-F), across all major fern lineages. We also present plastid barcode data for two genera in the hyperdiverse polypod clade--Deparia (Woodsiaceae) and the Cheilanthes marginata group (currently being segregated as a new genus of Pteridaceae)--to further evaluate the resolving power of these loci. PRINCIPAL FINDINGS: Our results clearly demonstrate the value of matK data, previously unavailable in ferns because of difficulties in amplification due to a major rearrangement of the plastid genome. With its high sequence variation, matK complements rbcL to provide a two-locus barcode with strong resolving power. With sequence variation comparable to matK, trnL-F appears to be a suitable alternative barcode region in ferns, and perhaps should be added to the core barcode region if universal primer development for matK fails. In contrast, trnH-psbA shows dramatically reduced sequence variation for the majority of ferns. This is likely due to the translocation of this segment of the plastid genome into the inverted repeat regions, which are known to have a highly constrained substitution rate. CONCLUSIONS: Our study provides the first endorsement of the two-locus barcode (rbcL+matK) in ferns, and favors trnL-F over trnH-psbA as a potential back-up locus. Future work should focus on gathering more fern matK sequence data to facilitate universal primer development.
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    Sex-specific incompatibility generates locus-specific rates of introgression between species.
    (Genetics, 2011-09) Fusco, Diana; Uyenoyama, Marcy K
    Disruption of interactions among ensembles of epistatic loci has been shown to contribute to reproductive isolation among various animal and plant species. Under the Bateson-Dobzhansky-Muller model, such interspecific incompatibility arises as a by-product of genetic divergence in each species, and the Orr-Turelli model indicates that the number of loci involved in incompatible interactions may "snowball" over time. We address the combined effect of multiple incompatibility loci on the rate of introgression at neutral marker loci across the genome. Our analysis extends previous work by accommodating sex specificity: differences between the sexes in the expression of incompatibility, in rates of crossing over between neutral markers and incompatibility loci, and in transmission of markers or incompatibility factors. We show that the evolutionary process at neutral markers in a genome subject to incompatibility selection is well approximated by a purely neutral process with migration rates appropriately scaled to reflect the influence of selection targeted to incompatibility factors. We confirm that in the absence of sex specificity and functional epistasis among incompatibility factors, the barrier to introgression induced by multiple incompatibility factors corresponds to the product of the barriers induced by the factors individually. A new finding is that barriers to introgression due to sex-specific incompatibility depart in general from multiplicativity. Our partitioning of variation in relative reproductive rate suggests that such departures derive from associations between sex and incompatibility and between sex and neutral markers. Concordant sex-specific incompatibility (for example, greater impairment of male hybrids or longer map lengths in females) induces lower barriers (higher rates of introgression) than expected under multiplicativity, and discordant sex-specific incompatibility induces higher barriers.
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    Structure-Function Analysis of Interallelic Complementation in ROOTY Transheterozygotes.
    (Plant physiology, 2020-07) Brumos, Javier; Bobay, Benjamin G; Clark, Cierra A; Alonso, Jose M; Stepanova, Anna N
    Auxin is a crucial plant growth regulator. Forward genetic screens for auxin-related mutants have led to the identification of key genes involved in auxin biosynthesis, transport, and signaling. Loss-of-function mutations in genes involved in glucosinolate biosynthesis, a metabolically related route that produces defense compounds, result in auxin overproduction. We identified an allelic series of fertile, hypomorphic Arabidopsis (Arabidopsis thaliana) mutants for the essential glucosinolate biosynthetic gene ROOTY (RTY) that exhibit a range of phenotypic defects characteristic of enhanced auxin production. Genetic characterization of these lines uncovered phenotypic suppression by cyp79b2 cyp79b3, wei2, and wei7 mutations and revealed the phenomenon of interallelic complementation in several RTY transheterozygotes. Structural modeling of RTY elucidated the relationships between structure and function in the RTY homo- and heterodimers, and unveiled the likely structural basis of interallelic complementation. This work underscores the importance of employing true null mutants in genetic complementation studies.
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    The evolutionary history of ferns inferred from 25 low-copy nuclear genes.
    (Am J Bot, 2015-07) Rothfels, CJ; Li, F; Sigel, EM; Huiet, L; Larsson, A; Burge, DO; Ruhsam, M; Deyholos, M; Soltis, DE; Stewart Jr, CN
    UNLABELLED: • PREMISE OF THE STUDY: Understanding fern (monilophyte) phylogeny and its evolutionary timescale is critical for broad investigations of the evolution of land plants, and for providing the point of comparison necessary for studying the evolution of the fern sister group, seed plants. Molecular phylogenetic investigations have revolutionized our understanding of fern phylogeny, however, to date, these studies have relied almost exclusively on plastid data.• METHODS: Here we take a curated phylogenomics approach to infer the first broad fern phylogeny from multiple nuclear loci, by combining broad taxon sampling (73 ferns and 12 outgroup species) with focused character sampling (25 loci comprising 35877 bp), along with rigorous alignment, orthology inference and model selection.• KEY RESULTS: Our phylogeny corroborates some earlier inferences and provides novel insights; in particular, we find strong support for Equisetales as sister to the rest of ferns, Marattiales as sister to leptosporangiate ferns, and Dennstaedtiaceae as sister to the eupolypods. Our divergence-time analyses reveal that divergences among the extant fern orders all occurred prior to ∼200 MYA. Finally, our species-tree inferences are congruent with analyses of concatenated data, but generally with lower support. Those cases where species-tree support values are higher than expected involve relationships that have been supported by smaller plastid datasets, suggesting that deep coalescence may be reducing support from the concatenated nuclear data.• CONCLUSIONS: Our study demonstrates the utility of a curated phylogenomics approach to inferring fern phylogeny, and highlights the need to consider underlying data characteristics, along with data quantity, in phylogenetic studies.
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    The genomic consequences of adaptive divergence and reproductive isolation between species of manakins.
    (Mol Ecol, 2013-06) Parchman, TL; Gompert, Z; Braun, MJ; Brumfield, RT; McDonald, DB; Uy, JAC; Zhang, G; Jarvis, ED; Schlinger, BA; Buerkle, CA
    The processes of adaptation and speciation are expected to shape genomic variation within and between diverging species. Here we analyze genomic heterogeneity of genetic differentiation and introgression in a hybrid zone between two bird species (Manacus candei and M. vitellinus) using 59 100 SNPs, a whole genome assembly, and Bayesian models. Measures of genetic differentiation (FST) and introgression (genomic cline center [α] and rate [β]) were highly heterogeneous among loci. We identified thousands of loci with elevated parameter estimates, some of which are likely to be associated with variation in fitness in Manacus populations. To analyze the genomic organization of differentiation and introgression, we mapped SNPs onto a draft assembly of the M. vitellinus genome. Estimates of FST, α, and β were autocorrelated at very short physical distances (< 100 bp), but much less so beyond this. In addition, average statistical associations (linkage disequilibrium) between SNPs were generally low and were not higher in admixed populations than in populations of the parental species. Although they did not occur with a constant probability across the genome, loci with elevated FST, α, and β were not strongly co-localized in the genome. Contrary to verbal models that predict clustering of loci involved in adaptation and isolation in discrete genomic regions, these results are consistent with the hypothesis that genetic regions involved in adaptive divergence and reproductive isolation are scattered throughout the genome. We also found that many loci were characterized by both exceptional genetic differentiation and introgression, consistent with the hypothesis that loci involved in isolation are also often characterized by a history of divergent selection. However, the concordance between isolation and differentiation was only partial, indicating a complex architecture and history of loci involved in isolation.
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    The Physarum polycephalum Genome Reveals Extensive Use of Prokaryotic Two-Component and Metazoan-Type Tyrosine Kinase Signaling.
    (Genome Biol Evol, 2015-11-27) Schaap, Pauline; Barrantes, Israel; Minx, Pat; Sasaki, Narie; Anderson, Roger W; Bénard, Marianne; Biggar, Kyle K; Buchler, Nicolas E; Bundschuh, Ralf; Chen, Xiao; Fronick, Catrina; Fulton, Lucinda; Golderer, Georg; Jahn, Niels; Knoop, Volker; Landweber, Laura F; Maric, Chrystelle; Miller, Dennis; Noegel, Angelika A; Peace, Rob; Pierron, Gérard; Sasaki, Taeko; Schallenberg-Rüdinger, Mareike; Schleicher, Michael; Singh, Reema; Spaller, Thomas; Storey, Kenneth B; Suzuki, Takamasa; Tomlinson, Chad; Tyson, John J; Warren, Wesley C; Werner, Ernst R; Werner-Felmayer, Gabriele; Wilson, Richard K; Winckler, Thomas; Gott, Jonatha M; Glöckner, Gernot; Marwan, Wolfgang
    Physarum polycephalum is a well-studied microbial eukaryote with unique experimental attributes relative to other experimental model organisms. It has a sophisticated life cycle with several distinct stages including amoebal, flagellated, and plasmodial cells. It is unusual in switching between open and closed mitosis according to specific life-cycle stages. Here we present the analysis of the genome of this enigmatic and important model organism and compare it with closely related species. The genome is littered with simple and complex repeats and the coding regions are frequently interrupted by introns with a mean size of 100 bases. Complemented with extensive transcriptome data, we define approximately 31,000 gene loci, providing unexpected insights into early eukaryote evolution. We describe extensive use of histidine kinase-based two-component systems and tyrosine kinase signaling, the presence of bacterial and plant type photoreceptors (phytochromes, cryptochrome, and phototropin) and of plant-type pentatricopeptide repeat proteins, as well as metabolic pathways, and a cell cycle control system typically found in more complex eukaryotes. Our analysis characterizes P. polycephalum as a prototypical eukaryote with features attributed to the last common ancestor of Amorphea, that is, the Amoebozoa and Opisthokonts. Specifically, the presence of tyrosine kinases in Acanthamoeba and Physarum as representatives of two distantly related subdivisions of Amoebozoa argues against the later emergence of tyrosine kinase signaling in the opisthokont lineage and also against the acquisition by horizontal gene transfer.
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    Uncoupling of genomic and epigenetic signals in the maintenance and inheritance of heterochromatin domains in fission yeast.
    (Genetics, 2012-02) Wheeler, Bayly S; Ruderman, Brandon T; Willard, Huntington F; Scott, Kristin C
    Many essential aspects of genome function, including gene expression and chromosome segregation, are mediated throughout development and differentiation by changes in the chromatin state. Along with genomic signals encoded in the DNA, epigenetic processes regulate heritable gene expression patterns. Genomic signals such as enhancers, silencers, and repetitive DNA, while required for the establishment of alternative chromatin states, have an unclear role in epigenetic processes that underlie the persistence of chromatin states throughout development. Here, we demonstrate in fission yeast that the maintenance and inheritance of ectopic heterochromatin domains are independent of the genomic sequences necessary for their de novo establishment. We find that both structural heterochromatin and gene silencing can be stably maintained over an ~10-kb domain for up to hundreds of cell divisions in the absence of genomic sequences required for heterochromatin establishment, demonstrating the long-term persistence and stability of this chromatin state. The de novo heterochromatin, despite the absence of nucleation sequences, is also stably inherited through meiosis. Together, these studies provide evidence for chromatin-dependent, epigenetic control of gene silencing that is heritable, stable, and self-sustaining, even in the absence of the originating genomic signals.