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1. The DNA sequence, annotation and analysis of human chromosome 3

Author

Zhengdong D. Zhang, Jun Wang, Zhu Chen, Will Gillett, George M. Weinstock, Guoping Zhao, LaRonda Jackson, Christopher K. Raymond, Manuel L. Gonzalez-Garay, Yang Zhou, Judith Hernandez, Boqin Qiang, James B. Clendenning, Zhijian J. Chen, Shannon Dugan-Rocha, Andrew R. Jackson, Zhijian Yao, Yan Shen, R. Alan Harris, Ziad Khan, Margaret Morgan, Wei Dong, Sharon Wei, Dawn Garcia, Aleksandar Milosavljevic, Maynard V. Olson, Ruben Rodriguez, Kerstin P. Clerc-Blankenburg, Ryan J. Lozado, Ralf Sudbrak, Jun Gu, Jing Kun Zhang, Heather R. Draper, Mary J. Brown, Channakhone Saenphimmachak, M. Ali Ansari-Lari, Songnian Hu, Preethi H. Gunaratne, Donna M. Muzny, Shiran Pasternak, Xing Zhi Song, Oliver Delgado, Bailin Hao, Lesette Perez, Charles Q. Adams, Michael L. Metzker, Anne Hodgson, Daniel Verduzco, Bao Viet Nguyen, Susan H. Kelly, Xin He, Jing Wang, Runsheng Chen, Karen A. Phelps, Rajinder Kaul, Guan Chen, Wei Huang, Huyen Dinh, Lenee Waldron, Paul Havlak, George Miner, Qiaoyan Wang, Ye Yuan, Rachel Gill, Anthony Palmeiri, Mathew W. Wright, Kim C. Worley, Michael Kube, Jing Liu, Clay Davis, Christian J. Buhay, Zhangwan Li, Jun Yu, Alicia Hawes, Jing Lu, Steffen Hennig, David L. Nelson, Rui Chen, Leni S. Jacob, Huanming Yang, Bin Liu, Steven E. Scherer, Christie Kovar-Smith, Jian Wang, Manjula Maheshwari, Gabrielle A. Williams, Paul E. Tabor, David A. Wheeler, Hans Lehrach, Graham R. Scott, Farah J.H. Plopper, Erica Sodergren, Wen Liu, Mulu Ayele, Richard Reinhardt, Richard A. Gibbs, Eric Haugen, Lora Lewis, Hua Shen, Gang Fu, Jianling Zhou, Xiuqing Zhang, Stephen Ernst, Geoffrey Okwuonu, Susan L. Naylor, Jennifer Hume, Ruth Levy, Andrew Cree, Yan Ding, David Steffen, Lynne V. Nazareth, Jireh Santibanez, Sandhya Subramanian, and Gane Ka-Shu Wong

Subjects
Inversion, Chromosome, Genome evolution, DNA, Complementary, Pan troglodytes, Molecular Sequence Data, Biology, Synteny, Genome, Evolution, Molecular, Chimpanzee genome project, Contig Mapping, Chromosome 19, Human Genome Project, Animals, Humans, Expressed Sequence Tags, Genetics, Multidisciplinary, Base Sequence, Chromosome Breakage, Sequence Analysis, DNA, Genome project, Macaca mulatta, Chromosome Inversion, CpG Islands, Human genome, Chromosomes, Human, Pair 3, Chromosome 21, Reference genome
Abstract

Udgivelsesdato: 2006-Apr-27 After the completion of a draft human genome sequence, the International Human Genome Sequencing Consortium has proceeded to finish and annotate each of the 24 chromosomes comprising the human genome. Here we describe the sequencing and analysis of human chromosome 3, one of the largest human chromosomes. Chromosome 3 comprises just four contigs, one of which currently represents the longest unbroken stretch of finished DNA sequence known so far. The chromosome is remarkable in having the lowest rate of segmental duplication in the genome. It also includes a chemokine receptor gene cluster as well as numerous loci involved in multiple human cancers such as the gene encoding FHIT, which contains the most common constitutive fragile site in the genome, FRA3B. Using genomic sequence from chimpanzee and rhesus macaque, we were able to characterize the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae, and propose an evolutionary history of the inversion.

Published
2006
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2. The DNA sequence of the human X chromosome

Author

Gernot Glöckner, Karen Thomas, Christine Lloyd, Huda Y. Zoghbi, Adrienne Hunt, Fiona Francis, Annemarie Poustka, George M. Weinstock, Xuehong Wei, Alan Tracey, Gabriele Nordsiek, Ines Müller, Graham Clarke, Oliver Beasley, John Sulston, Alfred Beck, Christian J. Buhay, Thomas Meitinger, Manjula Maheshwari, Yvonne Ramsey, Kirsten McLay, Shannon Dugan-Rocha, James G. R. Gilbert, Louisa Faulkner, Sidney Morris, Margaret Morgan, Huntington F. Willard, Leni S. Jacob, Hermela Loulseged, K M Porter, T. Daniel Andrews, Cordelia Langford, Paul Wray, Guan Chen, Juliane Ramser, Nigel P. Carter, Georgina Warry, Ruby Banerjee, Graeme Bethel, LaDeana W. Hillier, Anne Hodgson, Stephen M. J. Searle, K F Barlow, David R. Bentley, Paul E. Tabor, Kathryn L. Evans, Russell J. Grocock, Rebecca Woodmansey, Alex V Pearce, Christie Kovar-Smith, Angela Williamson, Dean Chavez, Roy Storey, Kevin L. Howe, Zhijian J. Chen, Lesette Perez, Richard A. Gibbs, Michele D'Urso, Karen N Bates, Jackie Bye, Shirin S. Joseph, Bernd Hinzmann, Paul Heath, Susan H. Kelly, Jennifer Hume, Paula E. Burch, David Buck, Mark T. Ross, David A. Wheeler, Matthew C. Jones, A K Babbage, Erica Sodergren, Sophie Palmer, Jie Ma, Elizabeth C. Sotheran, Margaret A. Leversha, Cerissa Hamilton, Hans Lehrach, Swaroop Aradhya, Michael L. Metzker, S. M. Clegg, Elizabeth J. Huckle, Audrey Fraser, Sarah Bray-Allen, C. D. Skuce, Petra Galgoczy, Richard K. Wilson, Patrick Minx, Richard E Connor, Tamsin Eades, Alfons Meindl, Michelle Smith, John M. Davis, André Rosenthal, Stuart McLaren, Geoffery Okwuonu, M. Vaudin, Laura Carrel, Ryan J. Lozado, Harminder Sehra, Richard Pandian, Sue Y Clark, Anna Kosiura, Wen Liu, Simon G. Gregory, A Tromans, Alexandra Emery-Cohen, Charles Shaw-Smith, Donna Villasana, Joseph Chako, Katja Heitmann, Robert G. David, Jennifer L. Ashurst, Craig Chinault, S Lawlor, Paul Havlak, Jane E. Loveland, Lucy Matthews, Jianling Zhou, S. Whitehead, Paul Hunt, E Sheridan, Richard Reinhardt, Tim Hubbard, Mary G. Schueler, Patrick Meidl, Helen Beasley, David Beare, Donna M. Muzny, Kerry A Ridler, Joanne C Chapman, Jennifer McDowall, Andrew Dunham, Anne Bridgeman, Gabrielle Williams, Amanda McMurray, Stefan Taudien, Matthew E. Hurles, Helen Williamson, Preethi H. Gunaratne, Alfredo Ciccodicola, R Ainscough, Alison J. Coffey, Charlotte G. Cole, Stephan Beck, Frances L Lovell, Alan Coulson, Qiaoyan Wang, Sally Jones, Charles A. Steward, Michael Hoffs, Kim C. Worley, Sarah Pelan, David Bonnin, David Schlessinger, Mathew N Whiteley, Graham Scott, Christopher N O'Dell, Tineace Taylor, Susan Rhodes, Anthony P. West, E. Hart, Ian P. Barrett, Andrea Thorpe, D. Pearson, Huyen Dinh, Susan M. Gribble, Andrew J Knights, Laurens G. Wilming, N Corby, Steven E. Scherer, Pawandeep Dhami, Gerald Nyakatura, J Lovell, M. Ali Ansari-Lari, Kerstin P. Clerc-Blankenburg, David Swarbreck, Sara Zorilla, Yanghong Gu, Karin Blechschmidt, Matthew Dunn, Andrew Brown, Kirsten M. Timms, Darren Grafham, Yan Ding, Elspeth A. Bruford, Leanne Williams, Melanie M. Wall, Hua Shen, Dina Patel, Joanne K Kershaw, Rachel Gill, Yuan Chen, Joy Davies, D C Burford, John Burton, Vicky Cobley, R I S Ashwell, Nicola Brady, Ellson Y. Chen, Ngoc Nguyen, Gaiping Wen, Gavin K. Laird, Julia E. Parrish, Carol Scott, C Griffiths, Ratna Shownkeen, Ralf Sudbrak, Denise R. DeShazo, Shiran Pasternak, Ireena Dutta, Brian Teague, Rachael Lyne, David Parker, Jane Rogers, Steve Dodsworth, Mary J. Brown, Gary E Barker, Steve Trevanion, Joanne Burgess, Jane E. Wilkinson, James T. Warren, Jen S. Conquer, R Mark Swann, Oliver Delgado, Heather R. Draper, Shailesh L Mistry, Chris Clee, Richard Durbin, Karen Clifford, John Frankland, Sarah E. Hunt, David Steffen, Christine Burrows, Daniel Verduzco, C Carder, Robert H. Waterston, Stephen Richards, Andrea Ballabio, Catherine M. Rice, David Willey, Helen Errington, Andrew Cree, K. James Durbin, Lora Lewis, D. M. Lloyd, Helen E. Steingruber, Adam Whittaker, K D Ambrose, Rhian Gwilliam, Adam Frankish, Robert S. Fulton, Judith Hernandez, Claire L Bagguley, Pieter J. de Jong, Jennifer Yen, Matthew Ellwood, Christine P. Bird, Rui Chen, Sarah Milne, Clay Davis, Alicia Hawes, Jing Lu, Sven Klages, David L. Nelson, Wayne Burrill, Jingkun Zhang, Judith Isherwood, Kathrin Reichwald, Lenee Waldron, Rebecca Deadman, Steffen Hennig, Ziad Khan, Sarah Ho, Matthias Platzer, Gareth R. Howell, Stephen Keenan, Petra Kioschis, Phillip J Howden, George Miner, David W. Johnson, and James C. Mullikin

Subjects
Male, Genetic Linkage, Genetics, Medical, Centromere, HUMAN GENOME SEQUENCE, Biology, Y chromosome, Polymorphism, Single Nucleotide, Article, Evolution, Molecular, Contig Mapping, Chromosome 16, Antigens, Neoplasm, Dosage Compensation, Genetic, Sequence Homology, Nucleic Acid, Chromosome 19, Testis, Animals, Humans, Crossing Over, Genetic, X chromosome, Repetitive Sequences, Nucleic Acid, Genetics, Chromosomes, Human, X, Chromosomes, Human, Y, Multidisciplinary, INACTIVATION CENTER, LINKED MENTAL-RETARDATION, Genomics, Sequence Analysis, DNA, REPEAT HYPOTHESIS, MAMMALIAN Y-CHROMOSOME, Chromosome 4, Chromosome 3, RNA, Female, Chromosome 21, Chromosome 22
Abstract

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.

Published
2005
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3. Common and rare variants of DAOA in bipolar disorder

Author

David A. Wheeler, Elliot S. Gershon, Andrew D. Skol, Judith A. Badner, Fowler R. Gerald, Manjula Maheshwari, Francis J. McMahon, Donna M. Muzny, James B. Potash, Jiajun Shi, Sevilla D. Detera-Wadleigh, Richard A. Gibbs, Chunyu Liu, and Virginia L. Willour

Subjects
Genetics, Male, Bipolar Disorder, Positional cloning, Intracellular Signaling Peptides and Proteins, Single-nucleotide polymorphism, Exons, Sequence Analysis, DNA, Biology, Polymorphism, Single Nucleotide, Genetic determinism, Article, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Genotype, SNP, Humans, Female, Genetic Predisposition to Disease, Allele, Cloning, Molecular, Carrier Proteins, Genotyping, Genetics (clinical), Genetic association
Abstract

The d-amino acid oxidase activator (DAOA, previously known as G72) gene, mapped on 13q33, has been reported to be genetically associated with bipolar disorder (BP) in several populations. The consistency of associated variants is unclear and rare variants in exons of the DAOA gene have not been investigated in psychiatric diseases. We employed a conditional linkage method - STatistical Explanation for Positional Cloning (STEPC) to evaluate whether any associated single nucleotide polymorphisms (SNPs) account for the evidence of linkage in a pedigree series that previously has been linked to marker D13S779 at 13q33. We also performed an association study in a sample of 376 Caucasian BP parent-proband trios by genotyping 38 common SNPs in the gene region. Besides, we resequenced coding regions and flanking intronic sequences of DAOA in 555 Caucasian unrelated BP patients and 564 mentally healthy controls, to identify putative functional rare variants that may contribute to disease. One SNP rs1935058 could “explain” the linkage signal in the family sample set (P = 0.055) using STEPC analysis. No significant allelic association was detected in an association study by genotyping 38 common SNPs in 376 Caucasian BP trios. Reseqencing identified 53 SNPs, of which 46 were novel SNPs. There was no significant excess of rare variants in cases relative to controls. Our results suggest that DAOA does not have a major effect on BP susceptibility. However, DAOA may contribute to bipolar susceptibility in some specific families as evidenced by the STEPC analysis.

Published
2009

4. Sequence variation in DOCK9 and heterogeneity in bipolar disorder

Author

Elliot S. Gershon, Imer Cardona, Winston Corona, Nirmala Akula, Judith A. Badner, C. J. M. Steele, James B. Potash, Layla Kassem, Francis J. McMahon, Richard A. Gibbs, Chunyu Liu, Mukta Kundu, Sevilla D. Detera-Wadleigh, and Manjula Maheshwari

Subjects
Male, Psychosis, Bipolar Disorder, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Severity of Illness Index, Linkage Disequilibrium, Racing thoughts, Genetics, medicine, Guanine Nucleotide Exchange Factors, Humans, Family, Genetic Predisposition to Disease, Bipolar disorder, Biological Psychiatry, Genetics (clinical), Genetic heterogeneity, Linkage Disequilibrium Mapping, Genetic Variation, medicine.disease, Psychiatry and Mental health, Phenotype, Female, medicine.symptom, Mania
Abstract

BACKGROUND Linkage of bipolar disorder to a broad region on chromosome 13q has been supported in several studies including a meta-analysis on genome scans. Subsequent reports have shown that variations in the DAOA (G72) locus on 13q33 display association with bipolar disorder but these may not account for all of the linkage evidence in the region. OBJECTIVE To identify additional susceptibility loci on 13q32-q33 by linkage disequilibrium mapping and explore the impact of phenotypic heterogeneity on association. METHODS In the initial phase, 98 single nucleotide polymorphism (SNPs) located on 13q32-q33 were genotyped on 285 probands with bipolar disorder and their parents were drawn from families in the NIMH Genetics Initiative consortium for bipolar disorder (NIMH1-4) and two other series. Fine scale mapping using one family series (NIMH1-2) as the test sample was targeted on a gene that displayed the highest evidence of association. A secondary analysis of familial component phenotypes of bipolar disorder was conducted. RESULTS Three of seven SNPs in DOCK9, a gene that encodes an activator of the Rho-GTPase Cdc42, showed significant excess allelic transmission (P=0.0477-0.00067). Fine scale mapping on DOCK9 yielded evidence of association at nine SNPs in the gene (P=0.02-0.006). Follow-up tests detected excess transmission of the same allele of rs1340 in two out of three other sets of families. The association signals were largely attributable to maternally transmitted alleles (rs1927568: P=0.000083; odds ratio=3.778). A secondary analysis of familial component phenotypes of bipolar disorder detected significant association across multiple DOCK9 markers for racing thoughts, psychosis, delusion during mania and course of illness indicators. CONCLUSION These results suggest that DOCK9 contributes to both risk and increased illness severity in bipolar disorder. We found evidence for the effect of phenotypic heterogeneity on association. To our knowledge this is the first report to implicate DOCK9 or the Rho-GTPase pathway in the etiology of bipolar disorder.

Published
2007

5. The finished DNA sequence of human chromosome 12

Author

Steven E, Scherer, Donna M, Muzny, Christian J, Buhay, Rui, Chen, Andrew, Cree, Yan, Ding, Shannon, Dugan-Rocha, Rachel, Gill, Preethi, Gunaratne, R Alan, Harris, Alicia C, Hawes, Judith, Hernandez, Anne V, Hodgson, Jennifer, Hume, Andrew, Jackson, Ziad Mohid, Khan, Christie, Kovar-Smith, Lora R, Lewis, Ryan J, Lozado, Michael L, Metzker, Aleksandar, Milosavljevic, George R, Miner, Kate T, Montgomery, Margaret B, Morgan, Lynne V, Nazareth, Graham, Scott, Erica, Sodergren, Xing-Zhi, Song, David, Steffen, Ruth C, Lovering, David A, Wheeler, Kim C, Worley, Yi, Yuan, Zhengdong, Zhang, Charles Q, Adams, M Ali, Ansari-Lari, Mulu, Ayele, Mary J, Brown, Guan, Chen, Zhijian, Chen, Kerstin P, Clerc-Blankenburg, Clay, Davis, Oliver, Delgado, Huyen H, Dinh, Heather, Draper, Manuel L, Gonzalez-Garay, Paul, Havlak, Laronda R, Jackson, Leni S, Jacob, Susan H, Kelly, Li, Li, Zhangwan, Li, Jing, Liu, Wen, Liu, Jing, Lu, Manjula, Maheshwari, Bao-Viet, Nguyen, Geoffrey O, Okwuonu, Shiran, Pasternak, Lesette M, Perez, Farah J H, Plopper, Jireh, Santibanez, Hua, Shen, Paul E, Tabor, Daniel, Verduzco, Lenee, Waldron, Qiaoyan, Wang, Gabrielle A, Williams, Jingkun, Zhang, Jianling, Zhou, Carlana C, Allen, Anita G, Amin, Vivian, Anyalebechi, Michael, Bailey, Joseph A, Barbaria, Kesha E, Bimage, Nathaniel P, Bryant, Paula E, Burch, Carrie E, Burkett, Kevin L, Burrell, Eliana, Calderon, Veronica, Cardenas, Kelvin, Carter, Kristal, Casias, Iracema, Cavazos, Sandra R, Cavazos, Heather, Ceasar, Joseph, Chacko, Sheryl N, Chan, Dean, Chavez, Constantine, Christopoulos, Joseph, Chu, Raynard, Cockrell, Caroline D, Cox, Michelle, Dang, Stephanie R, Dathorne, Robert, David, Candi Mon'Et, Davis, Latarsha, Davy-Carroll, Denise R, Deshazo, Jeremy E, Donlin, Lisa, D'Souza, Kristy A, Eaves, Amy, Egan, Alexandra J, Emery-Cohen, Michael, Escotto, Nicole, Flagg, Lisa D, Forbes, Abdul M, Gabisi, Melissa, Garza, Cerissa, Hamilton, Nicholas, Henderson, Omar, Hernandez, Sandra, Hines, Marilyn E, Hogues, Mei, Huang, DeVincent G, Idlebird, Rudy, Johnson, Angela, Jolivet, Sally, Jones, Ryan, Kagan, Laquisha M, King, Belita, Leal, Heather, Lebow, Sandra, Lee, Jaclyn M, LeVan, Lakeshia C, Lewis, Pamela, London, Lorna M, Lorensuhewa, Hermela, Loulseged, Demetria A, Lovett, Alice, Lucier, Raymond L, Lucier, Jie, Ma, Renita C, Madu, Patricia, Mapua, Ashley D, Martindale, Evangelina, Martinez, Elizabeth, Massey, Samantha, Mawhiney, Michael G, Meador, Sylvia, Mendez, Christian, Mercado, Iracema C, Mercado, Christina E, Merritt, Zachary L, Miner, Emmanuel, Minja, Teresa, Mitchell, Farida, Mohabbat, Khatera, Mohabbat, Baize, Montgomery, Niki, Moore, Sidney, Morris, Mala, Munidasa, Robin N, Ngo, Ngoc B, Nguyen, Elizabeth, Nickerson, Ogechi O, Nwaokelemeh, Stanley, Nwokenkwo, Melissa, Obregon, Maryann, Oguh, Njideka, Oragunye, Rodolfo J, Oviedo, Bridgette J, Parish, David N, Parker, Julia, Parrish, Kenya L, Parks, Heidie A, Paul, Brett A, Payton, Agapito, Perez, William, Perrin, Adam, Pickens, Eltrick L, Primus, Ling-Ling, Pu, Maria, Puazo, Miyo M, Quiles, Juana B, Quiroz, Dina, Rabata, Kacy, Reeves, San Juana, Ruiz, Hongmei, Shao, Ida, Sisson, Titilola, Sonaike, Richard P, Sorelle, Angelica E, Sutton, Amanda F, Svatek, Leah Anne, Svetz, Kavitha S, Tamerisa, Tineace R, Taylor, Brian, Teague, Nicole, Thomas, Rachel D, Thorn, Zulma Y, Trejos, Brenda K, Trevino, Ogechi N, Ukegbu, Jeremy B, Urban, Lydia I, Vasquez, Virginia A, Vera, Donna M, Villasana, Ling, Wang, Stephanie, Ward-Moore, James T, Warren, Xuehong, Wei, Flower, White, Angela L, Williamson, Regina, Wleczyk, Hailey S, Wooden, Steven H, Wooden, Jennifer, Yen, Lillienne, Yoon, Vivienne, Yoon, Sara E, Zorrilla, David, Nelson, Raju, Kucherlapati, George, Weinstock, and Richard A, Gibbs

Subjects
Pan troglodytes, Molecular Sequence Data, Biology, Synteny, Linkage Disequilibrium, Evolution, Molecular, Chromosome 16, Chromosome 19, Animals, Humans, Sequence Deletion, Short Interspersed Nucleotide Elements, Genetics, Chromosome 7 (human), Expressed Sequence Tags, Base Composition, Multidisciplinary, Chromosomes, Human, Pair 12, Sequence Analysis, DNA, Chromosome 17 (human), Mutagenesis, Insertional, Chromosome 4, Chromosome 3, Genes, Evolutionary biology, CpG Islands, Chromosome 21, Chromosome 22, Microsatellite Repeats
Abstract

Human chromosome 12 contains more than 1,400 coding genes and 487 loci that have been directly implicated in human disease. The q arm of chromosome 12 contains one of the largest blocks of linkage disequilibrium found in the human genome. Here we present the finished sequence of human chromosome 12, which has been finished to high quality and spans approximately 132 megabases, representing approximately 4.5% of the human genome. Alignment of the human chromosome 12 sequence across vertebrates reveals the origin of individual segments in chicken, and a unique history of rearrangement through rodent and primate lineages. The rate of base substitutions in recent evolutionary history shows an overall slowing in hominids compared with primates and rodents.

Published
2005

6. Mutation screening of two candidate genes from 13q32 in families affected with Bipolar disorder: human peptide transporter (SLC15A1) and human glypican5 (GPC5)

Author

Manjula Maheshwari, Richard A. Gibbs, Susan L. Christian, Chunyu Liu, Elliot S. Gershon, Judith A. Badner, and Sevilla D. Detera-Wadleigh

Subjects
Untranslated region, Candidate gene, lcsh:QH426-470, Bipolar disorder, lcsh:Biotechnology, Biology, Mutation screening, 03 medical and health sciences, Exon, Genetic linkage, lcsh:TP248.13-248.65, mental disorders, Genetics, Coding region, Gene, 030304 developmental biology, Genomic organization, 0303 health sciences, 030305 genetics & heredity, lcsh:Genetics, Mutation testing, GPC5, SLC15A1, Biotechnology, Research Article
Abstract

Background Multiple candidate regions as sites for Schizophrenia and Bipolar susceptibility genes have been reported, suggesting heterogeneity of susceptibility genes or oligogenic inheritance. Linkage analysis has suggested chromosome 13q32 as one of the regions with evidence of linkage to Schizophrenia and, separately, to Bipolar disorder (BP). SLC15A1 and GPC5 are two of the candidate genes within an approximately 10-cM region of linkage on chromosome 13q32. In order to identify a possible role for these candidates as susceptibility genes, we performed mutation screening on the coding regions of these two genes in 7 families (n-20) affected with Bipolar disorder showing linkage to 13q32. Results Genomic organization revealed 23 exons in SLC15A1 and 8 exons in GPC5 gene respectively. Sequencing of the exons did not reveal mutations in the GPC5 gene in the 7 families affected with BP. Two polymorphic variants were discovered in the SLC15A1 gene. One was T to C substitution in the third position of codon encoding alanine at 1403 position of mRNA in exon 17, and the other was A to G substitution in the untranslated region at position 2242 of mRNA in exon 23. Conclusions Mutation analysis of 2 candidate genes for Bipolar disorder on chromosome 13q32 did not identify any potentially causative mutations within the coding regions or splice junctions of the SLC15A1 or GPC5 genes in 7 families showing linkage to 13q32. Further studies of the regulatory regions are needed to completely exclude these genes as causative for Bipolar disorder.

Published
2002

7. Polymorphisms at the G72/G30 Gene Locus, on 13q33, Are Associated with Bipolar Disorder in Two Independent Pedigree Series*

Author

Richard A. Gibbs, Chunyu Liu, Sevilla D. Detera-Wadleigh, Judith A. Badner, Tom I. Bonner, Manjula Maheshwari, Eiji Hattori, Elliot S. Gershon, and Susan L. Christian

Subjects
Linkage disequilibrium, Bipolar Disorder, DNA, Complementary, Genetic Linkage, Molecular Sequence Data, Neurogenetics, Single-nucleotide polymorphism, Locus (genetics), Pedigree chart, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Genetic linkage, mental disorders, Genetics, Humans, Genetic Predisposition to Disease, Genetics(clinical), Allele frequency, Genetics (clinical), 030304 developmental biology, Likelihood Functions, 0303 health sciences, Chromosomes, Human, Pair 13, Haplotype, Intracellular Signaling Peptides and Proteins, Articles, Sequence Analysis, DNA, Pedigree, 3. Good health, Alternative Splicing, Genes, Haplotypes, Carrier Proteins, 030217 neurology & neurosurgery
Abstract

Linkage evidence suggests that chromosome 13 (13q32-33) contains susceptibility genes for both bipolar disorder and schizophrenia. Recently, genes called "G72" and "G30" were identified, and polymorphisms of these overlapping genes were reported to be associated with schizophrenia. We studied two series of pedigrees with bipolar disorder: the Clinical Neurogenetics (CNG) pedigrees (in which linkage to illness had been previously reported at 13q32-33), with 83 samples from 22 multiplex families, and the National Institute of Mental Health (NIMH) Genetics Initiative pedigrees, with 474 samples from 152 families. Sixteen single-nucleotide polymorphisms (SNPs) were genotyped at and around the G72/G30 locus, which covered a 157-kb region encompassing the entire complementary DNA sequences of G72 and G30. We performed transmission/disequilibrium testing (TDT) and haplotype analysis, since a linkage-disequilibrium block was present at this gene locus. In the CNG and NIMH data sets, the results of global TDT of the entire haplotype set were significant and consistent (P=.0004 and P=.008, respectively). In the CNG series, the associated genotypes divided the families into those with linkage and those without linkage (partitioned by the linkage evidence). Analysis of the decay of haplotype sharing gave a location estimate that included G72/G30 in its 95% confidence interval. Although statistically significant association was not detected for individual SNPs in the NIMH data set, the same haplotype was consistently overtransmitted in both series. These data suggest that a susceptibility variant for bipolar illness exists in the vicinity of the G72/G30 genes. Taken together with the earlier report, this is the first demonstration of a novel gene(s), discovered through a positional approach, independently associated with both bipolar illness and schizophrenia.

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