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1. Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimerʼs disease

Author

Lambert, J-C, Grenier-Boley, B, Harold, D, Zelenika, D, Chouraki, V, Kamatani, Y, Sleegers, K, Ikram, M A, Hiltunen, M, Reitz, C, Mateo, I, Feulner, T, Bullido, M, Galimberti, D, Concari, L, Alvarez, V, Sims, R, Gerrish, A, Chapman, J, Deniz-Naranjo, C, Solfrizzi, V, Sorbi, S, Arosio, B, Spalletta, G, Siciliano, G, Epelbaum, J, Hannequin, D, Dartigues, J-F, Tzourio, C, Berr, C, Schrijvers, E MC, Rogers, R, Tosto, G, Pasquier, F, Bettens, K, Van Cauwenberghe, C, Fratiglioni, L, Graff, C, Delepine, M, Ferri, R, Reynolds, C A, Lannfelt, L, Ingelsson, M, Prince, J A, Chillotti, C, Pilotto, A, Seripa, D, Boland, A, Mancuso, M, Bossù, P, Annoni, G, Nacmias, B, Bosco, P, Panza, F, Sanchez-Garcia, F, Del Zompo, M, Coto, E, Owen, M, OʼDonovan, M, Valdivieso, F, Caffara, P, Scarpini, E, Combarros, O, Buée, L, Campion, D, Soininen, H, Breteler, M, Riemenschneider, M, Van Broeckhoven, C, Alpérovitch, A, Lathrop, M, Trégouët, D-A, Williams, J, Amouyel, P, consortium, E ADI, and consortium, G ERAD

Published
2013
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3. Genetic Aspects of Epilepsy-Aphasia Syndromes

Author

Roll, P., Rudolf, G., Pereira, S., Royer, B., Scheffer, I. E., Valenti, M. P., Metz-Lutz, M. N., Delepine, M., Lévy, N., Berkovic, S. F., Hirsch, E., Lathrop, G. M., Cau, P., and Szepetowski, P.

Published
2005

4. Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. (Original Article)

Author

Van Maldergem, L., Magre, J., Khallouf, T.E., Gedde-Dahl, Jr., T., Delepine, M., Trygstad, O., Seemanova, E., Stephenson, T., Albott, C.S., Bonnici, F., Panz, V.R., Medina, J-L, Bogalho, P., Huet, F., Savasta, S., Verloes, A., Robert, J-J, Loret, H., de Kerdanet, M., Tubiana-Rufi, N., Megarbane, A., Maassen, J., Polak, M., Lacombe, D., Kahn, C.R., Silveira, E.L., D'Abronzo, F.H., Grigorescu, F., Lathrop, M., Capeau, J., and O'Rahilly, S.

Subjects
Gene mutations -- Health aspects -- Research -- Genetic aspects, Diabetes -- Genetic aspects -- Research, Medical genetics -- Research -- Health aspects, Lipodystrophy -- Genetic aspects -- Research, Somatotypes -- Genetic aspects -- Health aspects -- Research, Heart failure -- Causes of -- Genetic aspects -- Research, African Americans -- Health aspects -- Research, Health, Research, Genetic aspects, Causes of, Health aspects
Abstract

Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently been identified, predominantly [...]

Published
2002

6. Erratum: Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Author

Lambert, J-C, Grenier-Boley, B, Harold, D, Zelenika, D, Chouraki, V, Kamatani, Y, Sleegers, K, Ikram, M A, Hiltunen, M, Reitz, C, Mateo, I, Feulner, T, Bullido, M, Galimberti, D, Concari, L, Alvarez, V, Sims, R, Gerrish, A, Chapman, J, Deniz-Naranjo, C, Solfrizzi, V, Sorbi, S, Arosio, B, Spalletta, G, Siciliano, G, Epelbaum, J, Hannequin, D, Dartigues, J-F, Tzourio, C, Berr, C, Schrijvers, E M C, Rogers, R, Tosto, G, Pasquier, F, Bettens, K, Van Cauwenberghe, C, Fratiglioni, L, Graff, C, Delepine, M, Ferri, R, Reynolds, C A, Lannfelt, L, Ingelsson, M, Prince, J A, Chillotti, C, Pilotto, A, Seripa, D, Boland, A, Mancuso, M, Bossù, P, Annoni, G, Nacmias, B, Bosco, P, Panza, F, Sanchez-Garcia, F, Zompo, M Del, Coto, E, Owen, M, O'Donovan, M, Valdivieso, F, Caffara, P, Scarpini, E, Combarros, O, Buée, L, Campion, D, Soininen, H, Breteler, M, Riemenschneider, M, Van Broeckhoven, C, Alpérovitch, A, Lathrop, M, Trégouët, D-A, Williams, J, and Amouyel, P

Published
2013
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7. A novel Alzheimer disease locus located near the gene encoding tau protein

Author

Jun, G., Ibrahim-Verbaas, C.A., Vronskaya, M., Lambert, J.-., Chung, J., Naj, A.C., Kunkle, B.W., Wang, L.-., Bis, J.C., Bellenguez, C., Harold, D., Lunetta, K.L., Destefano, A.L., Grenier-Boley, B., Sims, R., Beecham, G.W., Smith, A.V., Chouraki, V., Hamilton-Nelson, K.L., Ikram, M.A., Fievet, N., Denning, N., Martin, E.R., Schmidt, H., Kamatani, Y., Dunstan, M.L., Valladares, O., Laza, A.R., Zelenika, D., Ramirez, A., Foroud, T.M., Choi, S.-., Boland, A., Becker, T., Kukull, W.A., Van Der Lee, S.J., Pasquier, F., Cruchaga, C., Beekly, D., Fitzpatrick, A.L., Hanon, O., Gill, M., Barber, R., Gudnason, V., Campion, D., Love, S., Bennett, D.A., Amin, N., Berr, C., Tsolaki, M., Buxbaum, J.D., Lopez, O.L., Deramecourt, V., Fox, N.C., Cantwell, L.B., Tárraga, L., Dufouil, C., Hardy, J., Crane, P.K., Eiriksdottir, G., Hannequin, D., Clarke, R., Evans, D., Mosley, T.H., Letenneur, L., Brayne, C., Maier, W., De Jager, P., Emilsson, V., Dartigues, J.-., Hampel, H., Kamboh, M.I., De Bruijn, R.F.A.G., Tzourio, C., Pastor, P., Larson, E.B., Rotter, J.I., O'Donovan, M.C., Montine, T.J., Nalls, M.A., Mead, S., Reiman, E.M., Jonsson, P.V., Holmes, C., St George-Hyslop, P.H., Boada, M., Passmore, P., Wendland, J.R., Schmidt, R., Morgan, K., Winslow, A.R., Powell, J.F., Carasquillo, M., Younkin, S.G., Jakobsdóttir, J., Kauwe, J.S.K., Wilhelmsen, K.C., Rujescu, D., Nöthen, M.M., Hofman, A., Jones, L., Haines, J.L., Psaty, B.M., Van Broeckhoven, C., Holmans, P., Launer, L.J., Mayeux, R., Lathrop, M., Goate, A.M., Escott-Price, V., Seshadri, S., Pericak-Vance, M.A., Amouyel, P., Williams, J., Van Duijn, C.M., Schellenberg, G.D., Farrer, L.A., Adams, P.M., Albert, M.S., Albin, R.L., Apostolova, L.G., Arnold, S.E., Asthana, S., Atwood, C.S., Baldwin, C.T., Barmada, M.M., Barnes, L.L., Beach, T.G., Becker, J.T., Bigio, E.H., Bird, T.D., Blacker, D., Boeve, B.F., Bowen, J.D., Boxer, A., Burke, J.R., Cairns, N.J., Cao, C., Carlson, C.S., Carlsson, C.M., Carney, R.M., Carrasquillo, M.M., Carroll, S.L., Chui, H.C., Clark, D.G., Corneveaux, J., Cribbs, D.H., Crocco, E.A., De Jager, P.L., Decarli, C., Dekosky, S.T., Yesim Demirci, F., Dick, M., Dickson, D.W., Doody, R.S., Duara, R., Ertekin-Taner, N., Faber, K.M., Fairchild, T.J., Fallon, K.B., Farlow, M.R., Ferris, S., Frosch, M.P., Galasko, D.R., Gearing, M., Geschwind, D.H., Ghetti, B., Gilbert, J.R., Glass, J.D., Graff-Radford, N.R., Green, R.C., Growdon, J.H., Hakonarson, H., Hamilton, R.L., Harrell, L.E., Head, E., Honig, L.S., Huebinger, R.M., Huentelman, M.J., Hulette, C.M., Hyman, B.T., Jarvik, G.P., Jicha, G.A., Jin, L., Karydas, A., Kaye, J.A., Kim, R., Koo, E.H., Kowall, N.W., Kramer, J.H., Laferla, F.M., Lah, J.J., Leverenz, J.B., Levey, A.I., Ge, L., Lieberman, A.P., Lin, C., Lyketsos, C.G., Mack, W.J., Marson, D.C., Martiniuk, F., Mash, D.C., Masliah, E., Mccormick, W.C., Mccurry, S.M., Mcdavid, A.N., Mckee, A.C., Mesulam, M., Miller, B.L., Miller, C.A., Miller, J.W., Morris, J.C., Mukherjee, S., Murrell, J.R., Myers, A.J., O'Bryant, S., Olichney, J.M., Pankratz, V.S., Parisi, J.E., Partch, A., Paulson, H.L., Perry, W., Peskind, E., Petersen, R.C., Pierce, A., Poon, W.W., Potter, H., Quinn, J.F., Raj, A., Raskind, M., Reisberg, B., Reisch, J.S., Reitz, C., Ringman, J.M., Roberson, E.D., Rogaeva, E., Rosen, H.J., Rosenberg, R.N., Royall, D.R., Sager, M.A., Sano, M., Saykin, A.J., Schneider, J.A., Schneider, L.S., Seeley, W.W., Smith, A.G., Sonnen, J.A., Spina, S., Stern, R.A., Tanzi, R.E., Thornton-Wells, T.A., Trojanowski, J.Q., Troncoso, J.C., Tsuang, D.W., Van Deerlin, V.M., Van Eldik, L.J., Vardarajan, B.N., Vinters, H.V., Vonsattel, J.P., Weintraub, S., Welsh-Bohmer, K.A., Williamson, J., Wishnek, S., Woltjer, R.L., Wright, C.B., Chuang-Kuo, W., Chang-En, Y., Lei, Y., Thomas, C., Gerrish, A., Chapman, J., Stretton, A., Morgan, A., Oldham, H., Owen, M.J., Kehoe, P.G., Medway, C., Brown, K., Lord, J., Turton, J., Hooper, N.M., Vardy, E., Warren, J.D., Schott, J.M., Uphill, J., Hollingworth, P., Ryan, N., Rossor, M., Collinge, J., Ben-Shlomo, Y., Makrina, D., Gkatzima, O., Lupton, M., Koutroumani, M., Avramidou, D., Germanou, A., Jessen, F., Riedel-Heller, S., Dichgans, M., Heun, R., Kölsch, H., Schürmann, B., Herold, C., Lacour, A., Drichel, D., Hoffmann, P., Kornhuber, J., Wei, G., Feulner, T., Mayhaus, M., Pichler, S., Riemenschneider, M., van den Bussche, H., Lawlor, B., Lynch, A., Mann, D., Smith, A.D., Warden, D., Wilcock, G., Heuser, I., Wiltfang, J., Frölich, L., Hüll, M., Mayo, K., Livingston, G., Bass, N.J., Gurling, H., Mcquillin, A., Gwilliam, R., Deloukas, P., Al-Chalabi, A., Shaw, C.E., Singleton, A.B., Guerreiro, R., Russo, G., Jöckel, K., Moebus, S., Klopp, N., Wichmann, H.-., Li, M., Bisceglio, G., Fisher, E., Warner, N., Pickering-Brown, S., Craig, D., Johnston, J.A., Mcguinness, B., Todd, S., Rubinsztein, D.C., Lovestone, S., Bayer, A., Gallacher, J., Proitsi, P., Ortega-Cubero, Saraadams, P., Albert, M., Albin, R., Apostolova, L., Arnold, S., Atwood, C., Baldwin, C., Barmada, M., Barnes, L., Beach, T., Becker, J., Bigio, E., Bird, T., Boeve, B., Bowen, J., Burke, J., Cairns, N., Carlson, C., Carlsson, C., Carney, R., Carrasquillo, M., Carroll, S., Chui, H., Clark, D., Cribbs, D., Crocco, E., De Jager PL, Dekosky, S., Demirci, F., Dickson, D., Doody, R., Faber, K., Fairchild, T., Fallon, K., Farlow, M., Frosch, M., Galasko, D., Geschwind, D., Gilbert, J., Glass, J., Graff-Radford, N., Green, R., Growdon, J., Hamilton, R., Harrell, L., Honig, L., Huebinger, R., Huentelman, M., Hulette, C., Hyman, B., Jarvik, G., Jicha, G., Kauwe, J., Kaye, J., Koo, E., Kowall, N., Kramer, J., Laferla, F., Lah, J., Leverenz, J., Levey, A., Li, G., Lieberman, A., Lopez, O., Lyketsos, C., Mack, W., Marson, D., Mash, D., Mccormick, W., Mccurry, S., Mcdavid, A., Mckee, A., Miller, B., Miller, C., Miller, J., Morris, J., Murrell, J., Myers, A., Olichney, J., Pankratz, V., Parisi, J., Paulson, H., Petersen, R., Poon, W., Quinn, J., Reisch, J., Ringman, J., Roberson, E., Rosen, H., Rosenberg, R., Royall, D., Sager, M., Saykin, A., Schneider, J., Schneider, L., Seeley, W., Smith, A., Sonnen, J., Stern, R., Tanzi, R., Thornton-Wells, T., Trojanowski, J., Troncoso, J., Tsuang, D., Van Deerlin VM, Van Eldik LJ, Vardarajan, B., Vinters, H., Vonsattel, J., Welsh-Bohmer, K., Woltjer, R., Wright, C., Wu, C., Yu, C., Yu, L., Au, R., Wolf, P., Beiser, A., Satizabal, C., Uitterlinden, A., Rivadeneira, F., Koudstaal, P., Longstreth WT Jr, Kuller, L., Lumley, T., Rice, K., Harris, T., Nalls, M., Marksteiner, J., Dal-Bianco, P., Töglhofer, A., Freudenberger, P., Ransmayr, G., Benke, T., Toeglhofer, A., Boerwinkle, E., Bressler, J., Fornage, M., Morón, F., Hernández, I., Roca, M., Mauleón, A., Alegret, M., Ramírez-Lorca, R., González-Perez, A., Alpérovitch, A., Alvarez, V., Barberger-Gateau, P., Bettens, K., Bossù, P., Brice, A., Bullido, M., Caffara, P., Clarimon, J., Combarros, O., Coto, E., Del Zampo, M., Delepine, M., Deniz Naranjo MC, Epelbaum, J., Fratiglioni, L., Galimberti, D., Graff, C., Hiltunen, M., Ingelsson, M., Keller, L., Lannfelt, L., Llèo, A., Mancuso, M., Mateo, I., Mecocci, P., Nacmias, B., Panza, F., Pilotto, A., Garcia, F., Scarpini, E., Seripa, D., Sleegers, K., Soininen, H., Sorbi, S., Spalletta, G., Wallon, D., Owen, M., Kehoe, P., Hooper, N., Warren, J., Schott, J., Gu, W., Bass, N., Shaw, C., Singleton, A., Wichmann, H., Ma, L., Johnston, J., Rubinsztein, D., Ortega-Cubero, S., Epidemiology, Neurology, and Internal Medicine

Subjects
0301 basic medicine, Apolipoprotein E, Apolipoprotein E4, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, genetics [Alzheimer Disease], MAPT protein, human, tau Proteins, Polymorphism, Single Nucleotide, Article, Chromosomes, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, Settore BIO/13 - Biologia Applicata, Humans, ddc:610, Polymorphism, Molecular Biology, Biology, genetics [Apolipoprotein E4], Genetic association, Temporal cortex, Genetics, Pair 17, Haplotype, Single Nucleotide, 3. Good health, Chromosome 17 (human), genetics [tau Proteins], Chemistry, 030104 developmental biology, Psychiatry and Mental Health, Chromosomes, Human, Pair 17, Genome-Wide Association Study, Settore MED/26 - Neurologia, Human medicine, Psychology, 030217 neurology & neurosurgery, Human
Abstract

APOE epsilon 4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE epsilon 4+ (10 352 cases and 9207 controls) and APOE epsilon 4 - (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE e4 status. Suggestive associations (P < 1x10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE epsilon 4+: 1250 cases and 536 controls; APOE epsilon 4 -: 718 cases and 1699 controls). Among APOE epsilon 4 - subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P = 5.8 x 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE epsilon 4+ subjects (CR1 and CLU) or APOE epsilon 4 - subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P = 1.6 x 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P

Published
2016

8. Deep sequencing of the trypanosoma cruzi GP63 surface proteases reveals diversity and diversifying selection among chronic and congenital Chagas disease patients

Author

Llewellyn, M.S., Messenger, L.A., Luquetti, A.O., Garcia, L., Torrico, F., Tavares, S.B.N., Cheaib, B., Derome, N., Delepine, M., Baulard, C., Deleuze, J.-F., Sauer, S., and Miles, M.A.

Subjects
Technology Platforms
Abstract

Background\ud \ud Chagas disease results from infection with the diploid protozoan parasite Trypanosoma cruzi. T. cruzi is highly genetically diverse, and multiclonal infections in individual hosts are common, but little studied. In this study, we explore T. cruzi infection multiclonality in the context of age, sex and clinical profile among a cohort of chronic patients, as well as paired congenital cases from Cochabamba, Bolivia and Goias, Brazil using amplicon deep sequencing technology.\ud \ud Methodology/ Principal Findings\ud \ud A 450bp fragment of the trypomastigote TcGP63I surface protease gene was amplified and sequenced across 70 chronic and 22 congenital cases on the Illumina MiSeq platform. In addition, a second, mitochondrial target—ND5—was sequenced across the same cohort of cases. Several million reads were generated, and sequencing read depths were normalized within patient cohorts (Goias chronic, n = 43, Goias congenital n = 2, Bolivia chronic, n = 27; Bolivia congenital, n = 20), Among chronic cases, analyses of variance indicated no clear correlation between intra-host sequence diversity and age, sex or symptoms, while principal coordinate analyses showed no clustering by symptoms between patients. Between congenital pairs, we found evidence for the transmission of multiple sequence types from mother to infant, as well as widespread instances of novel genotypes in infants. Finally, non-synonymous to synonymous (dn:ds) nucleotide substitution ratios among sequences of TcGP63Ia and TcGP63Ib subfamilies within each cohort provided powerful evidence of strong diversifying selection at this locus.\ud \ud Conclusions/Significance\ud \ud Our results shed light on the diversity of parasite DTUs within each patient, as well as the extent to which parasite strains pass between mother and foetus in congenital cases. Although we were unable to find any evidence that parasite diversity accumulates with age in our study cohorts, putative diversifying selection within members of the TcGP63I gene family suggests a link between genetic diversity within this gene family and survival in the mammalian host.

Published
2015

9. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders

Author

State, M., Leblond, C.S., Heinrich, J., Delorme, R., Proepper, C., Betancur, C., Huguet, G., Konyukh, M., Chaste, P., Ey, E., Rastam, M., Anckarsäter, H., Nygren, G., Gillberg, I.C., Melke, J., Toro, R., Regnault, B., Fauchereau, F., Mercati, O., Lemière, N., Skuse, D., Poot, M., Holt, R., Monaco, A.P., Järvelä, I., Kantojärvi, K., Vanhala, R., Curran, S., Collier, D.A., Bolton, P., Chiocchetti, A., Klauck, S.M., Poustka, F., Freitag, C.M., Waltes, R., Kopp, M., Duketis, E., Bacchelli, E., Minopoli, F., Ruta, L., Battaglia, A., Mazzone, L., Maestrini, E., Sequeira, A.F., Oliveira, B., Vicente, A., Oliveira, G., Pinto, D., Scherer, S.W., Zelenika, D., Delepine, M., Lathrop, M., Bonneau, D., Guinchat, V., Devillard, F., Assouline, B., Mouren, M., Leboyer, M., Gillberg, C., Boeckers, T.M., and Bourgeron, T.

Subjects
mental disorders
Abstract

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

Published
2012

10. LARGE-SCALE TEST OF HYPOTHESISED ASSOCIATIONS BETWEEN POLYMORPHISM OF LIPID-RELATED GENES AND MYOCARDIAL INFARCTION IN ABOUT 5000 CASES AND 6000 CONTROLS

Author

Keavney, B, Youngman, L, Palmer, A, Parish, S, Clark, S, Delepine, M, Lathrop, M, Peto, R, and Collins, R

Subjects
Heart diseases -- Risk factors -- Genetic aspects, Coronary heart disease -- Risk factors -- Genetic aspects, Risk factors (Health) -- Genetic aspects -- Health aspects, Genetic polymorphisms -- Health aspects -- Genetic aspects, Blood lipids -- Genetic aspects -- Health aspects, Health, Genetic aspects, Risk factors, Health aspects
Abstract

M Delepine [1] M Lathrop [1] Background: Some relatively small studies have reported associations between the risk of myocardial infarction (MI) and genotypes at polymorphism of genes related to blood [...]

Published
2001

11. A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium

Author

Horwitz, M.S., McKay, J.D., Truong, T., Gaborieau, V., Chabrier, A., Chuang, S.-C., Byrnes, G., Zaridze, D., Shangina, O., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Bucur, A., Bencko, V., Holcatova, I., Janout, V., Foretova, L., Lagiou, P., Trichopoulos, D., Benhamou, S., Bouchardy, C., Ahrens, W., Merletti, F., Richiardi, L., Talamini, R., Barzan, L., Kjaerheim, K., Macfarlane, G.J., Macfarlane, T.V., Simonato, L., Canova, C., Agudo, A., Castellsagué, X., Lowry, R., Conway, D.I., McKinney, P.A., Healy, C.M., Toner, M.E., Znaor, A., Curado, M.P., Koifman, S., Menezes, A., Wünsch-Filho, V., Neto, J.E., Garrote, L.F., Boccia, S., Cadoni, G., Arzani, D., Olshan, A.F., Weissler, M.C., Funkhouser, W.K., Luo, J., Lubiński, J., Trubicka, J., Lener, M., Oszutowska, D., Schwartz, S.M., Chen, C., Fish, S., Doody, D.R., Muscat, J.E., Lazarus, P., Gallagher, C.J., Chang, S.C., Zhang, Z.F., Wei, Q., Sturgis, E.M., Wang, L.E., Franceschi, S., Herrero, R., Kelsey, K.T., McClean, M.D., Marsit, C.J., Nelson, H.H., Romkes, M., Buch, S., Nukui, T., Zhong, S., Lacko, M., Manni, J.J., Peters, W.H.M., Hung, R.J., McLaughlin, J., Vatten, L., Njølstad, I., Goodman, G.E., Field, J.K., Liloglou, T., Vineis, P., Clavel-Chapelon, F., Palli, D., Tumino, R., Krogh, V., Panico, S., González, C.A., Quirós, J.R., Martínez, C., Navarro, C., Ardanaz, E., Larrañaga, N., Khaw, K.T., Key, T., Bueno-de-Mesquita, H. B., Peeters, P.H.M., Trichopoulou, A., Linseisen, J., Boeing, H., Hallmans, G., Overvad, K., Tjønneland, A., Kumle, M., Riboli, E., Välk, K., Vooder, T., Metspalu, A., Zelenika, D., Boland, A., Delepine, M., Foglio, M., Lechner, D., Blanché, H., Gut, I.G., Galan, P., Heath, S., Hashibe, M., Hayes, R.B., Boffetta, P., Lathrop, M., and Brennan, P.

Abstract

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

Published
2011

12. The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study

Author

Lambert, J., Sleegers, K., Gonzalez-Perez, A., Ingelsson, M., Beecham, G., Hiltunen, M., Combarros, O., Bullido, M., Brouwers, N., Bettens, K., Berr, C., Pasquier, F., Richard, F., Dekosky, S., Hannequin, D., Haines, J., Tognoni, G., Fievet, N., Dartigues, J., Tzourio, C., Engelborghs, S., Arosio, B., Coto, E., De Deyn, P., Del Zompo, M., Mateo, I., Boada, M., Antunez, C., Lopez-Arrieta, J., Epelbaum, J., Schjeide, B., Frank-Garcia, A., Giedraitis, V., Helisalmi, S., Porcellini, E., Pilotto, A., Forti, P., Ferri, R., Delepine, M., Zelenika, D., Lathrop, M., Scarpini, E., Siciliano, G., Solfrizzi, V., Sorbi, S., Spalletta, G., Ravaglia, G., Valdivieso, F., Vepsalainen, S., Alvarez, V., Bosco, P., Mancuso, M., Panza, F., Nacmias, B., Bossu, P., Hanon, O., Piccardi, P., Annoni, G., Mann, D., Marambaud, P., Seripa, D., Galimberti, D., Tanzi, R., Bertram, L., Lendon, C., Lannfelt, L., Licastro, F., Campion, D., Pericak-Vance, M., Soininen, H., Van Broeckhoven, C., Alperovitch, A., Ruiz, A., Kamboh, M., and Amouyel, P.

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the epsilon4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the epsilon4 allele of the APOE gene.

Published
2010

13. Genetic analysis of chromosome 2 in type 1 diabetes. Analysis of putative loci IDDM7, IDDM12 and IDDM13 and candidate genes NRAMP1 and IA-2 and the inteleukin-1 gene cluster

Author

Esposito L, Hill NJ, Pritchard LE, Cucca F, Muxworthy C, Merriman ME, Wilson A, Julier C, Delepine M, Tuomilehto J, Tuomilehto Wolf E, Ionesco Tirgoviste C, Nisticò L, IMDIAB Group, Buzzetti R, Pozzilli P, FERRARI, MAURIZIO, Pociot F, Nerup J, Bain SC, Todd JA, BOSI , EMANUELE, Esposito, L, Hill, Nj, Pritchard, Le, Cucca, F, Muxworthy, C, Merriman, Me, Wilson, A, Julier, C, Delepine, M, Tuomilehto, J, Tuomilehto Wolf, E, Ionesco Tirgoviste, C, Nisticò, L, Imdiab, Group, Buzzetti, R, Pozzilli, P, Ferrari, Maurizio, Bosi, Emanuele, Pociot, F, Nerup, J, Bain, Sc, and Todd, Ja

Published
1998

14. Lung cancer susceptibility locus at 5p15.33

Author

McKay, J.D. Hung, R.J. Gaborieau, V. Boffetta, P. Chabrier, A. Byrnes, G. Zaridze, D. Mukeria, A. Szeszenia-Dabrowska, N. Lissowska, J. Rudnai, P. Fabianova, E. Mates, D. Bencko, V. Foretova, L. Janout, V. McLaughlin, J. Shepherd, F. Montpetit, A. Narod, S. Krokan, H.E. Skorpen, F. Elvestad, M.B. Vatten, L. Njølstad, I. Axelsson, T. Chen, C. Goodman, G. Barnett, M. Loomis, M.M. Lubĩski, J. Matyjasik, J. Lener, M. Oszutowska, D. Field, J. Liloglou, T. Xinarianos, G. Cassidy, A. Zelenika, D. Boland, A. Delepine, M. Foglio, M. Lechner, D. Matsuda, F. Blanche, H. Gut, I. Heath, S. Lathrop, M. Brennan, P. Vineis, P. Clavel-Chapelon, F. Palli, D. Tumino, R. Krogh, V. Panico, S. González, C.A. Ramón Quirós, J. Martínez, C. Navarro, C. Ardanaz, E. Larrãaga, N. Kham, K.T. Key, T. Bueno-De-Mesquita, H.B. Peeters, P.H.M. Trichopoulou, A. Linseisen, J. Boeing, H. Hallmans, G. Overvad, K. Tjønneland, A. Kumle, M. Riboli, E.

Abstract

We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 × 10-7 and P = 4 × 10-6) and replicated by the independent study series (P = 7 × 10-5 and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology. © 2008 Nature Publishing Group.

Published
2008

15. Wolcott-Rallison syndrome - Clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity

Author

Senee, V, Vattem, KM, Delepine, M, Rainbow, LA, Haton, C, Lecoq, A, Shaw, NJ, and Çukurova Üniversitesi

Abstract

WOS: 000222397000030 PubMed ID: 15220213 Wolcott-Rallison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2alpha (eIF2alpha) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (

Published
2004

17. Multiple DNA Variant Association Analysis: Application to the Insulin Gene Region in Type 1 Diabetes

Author

Julier, C., Lucassen, A., Villedieu, P., Delepine, M., Levy-Marchal, C., Danzé, P. M., Bianchi, F., Boitard, C., Froguel, P., Bell, J., and Lathrop, G. M.

Subjects
Molecular Epidemiology, Diabetes Mellitus, Type 1, Genetic Variation, Humans, Insulin, Original Articles, Disease Susceptibility, France
Abstract

Association and linkage studies have shown that at least one of the genetic factors involved in susceptibility to insulin-dependent diabetes mellitus (IDDM) is contained within a 4.1-kb region of the insulin gene. Sequence analysis has led to the identification of 10 DNA variants in this region that are associated with increased risk for IDDM. These variants are in strong linkage disequilibrium with each other, and previous studies have failed to distinguish between the variant(s) that cause increased susceptibility to IDDM and others that are associated with the disease because of linkage disequilibrium. To address this problem, we have undertaken a large population study of French diabetics and controls and have analyzed genotype patterns for several of the variant sites simultaneously. This has led to the identification of a subset consisting of four variants (-2733AC, -23HphI, -365VNTR, and +1140AC), at least one of which appears to be directly implicated in disease susceptibility. The multiple-DNA-variant association-analysis approach that is applied here to the problem of identifying potential susceptibility variants in IDDM is likely to be important in studies of many other multifactorial diseases.

Published
1994

21. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis

Author

Lacombe Didier, Mom Thierry, Francannet Christine, Duvillard Alain, Thauvin Christel, Dubin Jacques, Bonneau Dominique, Montaut-Verient Bettina, Vigneron Jacqueline, Calais Catherine, David Albert, Eliot Marie-Madeleine, Dollfus Hélène, Vincent Christophe, Delobel Bruno, Weil Dominique, El-Amraoui Aziz, Jonard Laurence, Feldmann Delphine, Zelenika Diana, Délépine Marc, Niasme-Grare Magali, Parodi Marine, Hardelin Jean-Pierre, Levilliers Jacqueline, Marlin Sandrine, Grati M'hamed, Bonnet Crystel, Duriez Françoise, Drouin-Garraud Valérie, Thuillier-Obstoy Marie-Françoise, Sigaudy Sabine, Frances Anne-Marie, Collignon Patrick, Challe Georges, Couderc Rémy, Lathrop Mark, Sahel José-Alain, Weissenbach Jean, Petit Christine, and Denoyelle Françoise

Subjects
Medicine
Abstract

Abstract Background Usher syndrome (USH) combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3). Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool. Methods We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3). Results Biallelic mutations were detected in 39 patients (72%) and monoallelic mutations in an additional 10 patients (18.5%). In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%), and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48%) were novel. Conclusions Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.

Published
2011
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23. Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations

Author

Anne Boland, Giorgio Annoni, Elisa Porcellini, Gloria Tognoni, Giovanni Ravaglia, Mark Lathrop, Ignacio Mateo, Paola Bossù, Diana Zelenika, Nathalie Fievet, Marc Delepine, Mikko Hiltunen, Ana Frank-García, Hilkka Soininen, Paola Forti, Gianfranco Spalletta, Federico Licastro, Daniela Galimberti, Paola Piccardi, Maria Del Zompo, Seppo Helisalmi, Michelangelo Mancuso, Vincenzo Solfrizzi, Francesco Panza, Davide Seripa, Philippe Amouyel, María J. Bullido, Paolo Bosco, Gabriele Siciliano, Alberto Pilotto, Vincent Chouraki, Beatrice Arosio, Fernando Valdivieso, Jean-Charles Lambert, Elio Scarpini, Victoria Alvarez, Onofre Combarros, Sandro Sorbi, Benedetta Nacmias, Raffaele Ferri, Eliecer Coto, Lambert, J, Zelenika, D, Hiltunen, M, Chouraki, V, Combarros, O, Bullido, M, Tognoni, G, Fiévet, N, Boland, A, Arosio, B, Coto, E, Zompo, M, Mateo, I, Frank Garcia, A, Helisalmi, S, Porcellini, E, Pilotto, A, Forti, P, Ferri, R, Delepine, M, Scarpini, E, Siciliano, G, Solfrizzi, V, Sorbi, S, Spalletta, G, Ravaglia, G, Valdivieso, F, Alvarez, V, Bosco, P, Mancuso, M, Panza, F, Nacmias, B, Bossù, P, Piccardi, P, Annoni, G, Seripa, D, Galimberti, D, Licastro, F, Lathrop, M, Soininen, H, Amouyel, P, Lambert JC, Zelenika D, Hiltunen M, Chouraki V, Combarros O, Bullido MJ, Tognoni G, Fiévet N, Boland A, Arosio B, Coto E, Zompo MD, Mateo I, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Delepine M, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Ravaglia G, Valdivieso F, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Licastro F, Lathrop M, Soininen H, Amouyel P, and Universidad de Cantabria

Subjects
Apolipoprotein E, Aging, BIN1, Genotype, Disease, Biology, GWA, Polymorphism, Single Nucleotide, White People, PICALM, Polymorphism (computer science), Alzheimer Disease, Humans, Genetic Predisposition to Disease, Finland, Genetic Association Studies, Genetic association, Adaptor Proteins, Signal Transducing, Genetics, ALZHEIMER’S DISEASE, General Neuroscience, Tumor Suppressor Proteins, Nuclear Proteins, Odds ratio, POLYMORPHISM, Confidence interval, Italy, Spain, Monomeric Clathrin Assembly Proteins, Neurology (clinical), BIN1, PICALM, EXOC3L2, APOE, Alzheimer, Risk, GWA, Association, Polymorphism, Geriatrics and Gerontology, APOE, Developmental Biology
Abstract

Recent genome-wide association studies have identified 5 loci (BIM, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimer's disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CRI had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [Cl] [1.15-1.38], p = 2.9 X 10(-7), and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 X 10(-7), respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% Cl [1.06-1.32], p = 2.0 X 10(-3)). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN! and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation. (C) 2011 Elsevier Inc. All rights reserved.

Published
2011

24. A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium

Author

J. Ramón Quirós, Eva Ardanaz, Stefania Boccia, Wilbert H.M. Peters, Dimitrios Trichopoulos, Mario Foglio, Luigi Barzan, Lenka Foretova, Joshua E. Muscat, Françoise Clavel-Chapelon, Elio Riboli, Diana Zelenika, Paul Brennan, Salvatore Panico, Eleonora Fabianova, Lars J. Vatten, Kay-Tee Khaw, David I. Conway, Pilar Galan, Doris Lechner, Erich M. Sturgis, Shilong Zhong, Shama Buch, Jolanta Lissowska, Franco Merletti, Carmen Enid Martínez, Li E. Wang, H. Bas Bueno-de-Mesquita, Vittorio Krogh, Andres Metspalu, Anne Tjønneland, Shen Chih Chang, Rayjean J. Hung, Silvia Franceschi, Amelie Chabrier, Kristina Kjærheim, Gabriella Cadoni, Sergio Koifman, Ariana Znaor, Chu Chen, Pagona Lagiou, Ivana Holcatova, Richard B. Hayes, James McKay, Graham Byrnes, Philip Lazarus, Christine Bouchardy, Ray Lowry, Vladimir Bencko, Merethe Kumle, Jingchun Luo, Antonio Agudo, Mark Lathrop, David R. Doody, Victor Wünsch-Filho, Joanna Trubicka, Lorenzo Simonato, Martin Lacko, Cristina Canova, John K. Field, Sherianne Fish, Valerie Gaborieau, Xavier Castellsagué, Mary Toner, Thérèse Truong, Tomoko Nukui, Carla J. Gallagher, Wolfgang Ahrens, Triantafillos Liloglou, Kim Overvad, Vladimir Janout, Ivo Gut, Paolo Boffetta, Shu Chun Chuang, Göran Hallmans, Jakob Linseisen, Marjorie Romkes, David Zaridze, Mark C. Weissler, Simone Benhamou, Antonia Trichopoulou, Nerea Larrañaga, José Eluf Neto, Neonila Szeszenia-Dabrowska, Jan Lubinski, Stephen M. Schwartz, Peter Rudnai, Hélène Blanché, Mia Hashibe, William K. Funkhouser, Paolo Vineis, Maria Paula Curado, Gary J. Macfarlane, Marcin Lener, Claire M. Healy, Michael D. McClean, Domenico Palli, Marc Delepine, Tõnu Voodern, Carmen J. Marsit, Zuo-Feng Zhang, Kristjan Välk, Dorota Oszutowska, Heiner Boeing, Ana M. B. Menezes, Rolando Herrero, Leticia Fernández Garrote, Heather H. Nelson, Renato Talamini, Anne Boland, Alexandru Bucur, Qingyi Wei, Gary E. Goodman, Lorenzo Richiardi, Carmen Navarro, Karl T. Kelsey, Rosario Tumino, Inger Njølstad, Johannes J. Manni, Carlos A. González, Oxana Shangina, John R. McLaughlin, Patricia A. McKinney, Timothy J. Key, Andrew F. Olshan, Dario Arzani, Tatiana V. Macfarlane, Simon Heath, Petra H.M. Peeters, International Agency for Research on Cancer (IARC), Russian Academy of Medical Sciences, Department of Epidemiology, Institute of Occupational Medicine, Maria Skłodowska Curie Memorial Cancer Center, National Institute for Environment, Partenaires INRAE, Regional Authority of Public Health, Institute of Public Health, Charles University [Prague] (CU), Palacky University Olomouc, Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute (RECAMO), National and Kapodistrian University of Athens (NKUA), The Netherlands Cancer Institute, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université de Genève (UNIGE), Bremen Institute for Prevention Research and Social Medicine (BIPS), University of Bremen, Universita di Torino, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), General Hospital, Cancer Registry of Norway, School of Medicine and Dentistry, Universita di Padova, Imperial College London, Catalan Institute of Oncology, CIBER de Epidemiología y Salud Pública (CIBERESP), Newcastle University [Newcastle], Dental School, Centre for Epidemiology and Biostatistics, University of Leeds, NHS NSS ISD, School of Dental Science, University of Liverpool, National Institute of Public Health, National School of Public Health, Universidade Federal de Pelotas = Federal University of Pelotas (UFPel), Universidade de São Paulo (USP), Institute of Oncology and Radiobiology, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Institute of Hygiene, Università cattolica del Sacro Cuore [Milano] (Unicatt), University of North Carolina, Pomeranian Medical University, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Penn State College of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Penn State System, University of California [Los Angeles] (UCLA), University of California, Anderson Cancer Center, The University of Texas Health Science Center at Houston (UTHealth), Instituto de Investigación Epidemiológica, Brown University, School of public health, The University of Hong Kong (HKU), Masonic Cancer Center, University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, University of Pittsburgh (DEPARTMENT OF MATHEMATICS), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Maastricht University [Maastricht], Radboud University Medical Center [Nijmegen], Mount Sinai Hospital [Toronto, Canada] (MSH), Cancer Care Ontario, Norwegian University of Science and Technology (NTNU), University of Tromsø (UiT), Piedmont Reference Center for Epidemiology and Cancer Prevention, Department of Epidemiology and Public Health, Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto per lo Studio e la Prevezione Oncologica, Civile - M.P.Arezzo Hospital, Department of Clinical and Experimental Medicine, Università degli studi di Napoli Federico II, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université (HESAM)-HESAM Université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), INCa, France, US NCI [R01 CA092039 05/05S1], Benhamou, Simone, Bouchardy Magnin, Christine, Charles University in Prague, Università cattolica del Sacro Cuore [Roma] (Unicatt), Penn State System-Pennsylvania Commonwealth System of Higher Education (PCSHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), [McKay, JD, Truong, T, Gaborieau, V, Chabrier, A, Chuang, SC, Byrnes, G, Curado, MP, Franceschi, S, Hashibe, M, Boffetta, P, Brennan, P] IARC, Lyon, France. [Zaridze, D, Shangina, O] Russian Acad Med Sci, Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Szeszenia-Dabrowska, N] Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Lissowska, J] M Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Lissowska, J] Inst Oncol, Warsaw, Poland. [Rudnai, P] Natl Inst Environm Hlth, Budapest, Hungary. [Fabianova, E] Reg Author Publ Hlth, Banska Bystrica, Slovakia. [Bucur, A] Inst Publ Hlth, Bucharest, Romania. [Bencko, V, Holcatova, I] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague, Czech Republic. [Janout, V] Palacky Univ, CR-77147 Olomouc, Czech Republic. [Foretova, L] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Trichopoulos, D] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Benhamou, S] INSERM U946, Paris, France. [Benhamou, S] Inst Gustave Roussy, CNRS UMR8200, Villejuif, France. [Bouchardy, C] Univ Geneva, Geneva Canc Registry, Inst Social & Prevent Med, Geneva, Switzerland. [Ahrens, W] Univ Bremen, Bremen Inst Prevent Res & Social Med BIPS, Bremen, Germany. [Merletti, F, Richiardi, L] Univ Turin, Canc Epidemiol Unit, Turin, Italy. [Talamini, R] IRCCS, Natl Canc Inst, Aviano, Italy. [Barzan, L] Gen Hosp Pordenone, Pordenone, Italy. [Kjaerheim, K] Canc Registry Norway, Oslo, Norway. [Macfarlane, GJ, Macfarlane, TV] Univ Aberdeen, Sch Med & Dent, Aberdeen, Scotland. [Simonato, L, Canova, C] Univ Padua, Dept Environm Med & Publ Hlth, Padua, Italy. [Canova, C] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Agudo, A, Castellsague, X] ICO, Barcelona, Spain. [Castellsague, X, Navarro, C, Ardanaz, E] CIBERESP, Madrid, Spain. [Lowry, R] Univ Newcastle Dent Sch, Newcastle Upon Tyne, Tyne & Wear, England. [Conway, DI] Univ Glasgow Dent Sch, Glasgow, Lanark, Scotland. [McKinney, PA] Univ Leeds Ctr Epidemiol & Biostat, Leeds, W Yorkshire, England. [McKinney, PA] NHS NSS ISD, Edinburgh, Midlothian, Scotland. [Healy, CM, Toner, ME] Trinity Coll Sch Dent Sci, Dublin, Ireland. [Znaor, A] Croatian Natl Inst Publ Hlth, Croatian Natl Canc Registry, Zagreb, Croatia. [Koifman, S] Natl Sch Publ Hlth FIOCRUZ, Rio De Janeiro, Brazil. [Menezes, A] Univ Fed Pelotas, Pelotas, Brazil. [Wuensch, V, Neto, JE] Univ Sao Paulo, Sao Paulo, Brazil. [Garrote, LF] Inst Oncol & Radiobiol, Havana, Cuba. [Boccia, S, Cadoni, G, Arzani, D] Univ Cattolica Sacro Cuore, Inst Hyg, Rome, Italy. [Boccia, S] IRCCS San Raffaele Pisana, Rome, Italy. [Olshan, AF] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Weissler, MC, Funkhouser, WK, Luo, JC] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Lubinski, J, Trubicka, J, Lener, M, Oszutowska, D] Pomeranian Med Univ, Dept Genet & Pathomorphol, Int Hereditary Canc Ctr, Szczecin, Poland. [Oszutowska, D] Pomeranian Med Univ, Dept Hyg Epidemiol & Publ Hlth, Szczecin, Poland. [Schwartz, SM, Chen, C, Fish, S, Doody, DR, Goodman, GE] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Muscat, JE, Lazarus, P, Gallagher, CJ] Penn State Coll Med, Hershey, PA USA. [Chang, SC, Zhang, ZF] Univ Calif Los Angeles Sch Publ Hlth, Los Angeles, CA USA. [Wei, QY, Sturgis, EM, Wang, LE] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Herrero, R] Inst Invest Epidemiol, San Jose, Costa Rica. [Kelsey, KT, Marsit, CJ] Brown Univ, Providence, RI 02912 USA. [McClean, MD] Boston Univ Sch Publ Hlth, Boston, MA USA. [Nelson, HH] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN USA. [Romkes, M, Buch, S, Nukui, T, Zhong, SL] Univ Pittsburgh, Pittsburgh, PA USA. [Lacko, M, Manni, JJ] Maastricht Univ Med Ctr, Dept Otorhinolaryngol & Head & Neck Surg, Maastricht, Netherlands. [Peters, WHM] St Radboud Univ Nijmegen Med Ctr, Dept Gastroenterol, Nijmegen, Netherlands. [Hung, RJ] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [McLaughlin, J] Canc Care Ontario, Toronto, ON, Canada. [Vatten, L] Norwegian Univ Sci & Technol, N-7034 Trondheim, Norway. [Njolstad, I] Univ Tromso, Dept Community Med, Fac Hlth Sci, Tromso, Norway. [Field, JK, Liloglou, T] Univ Liverpool Canc Res Ctr, Roy Castle Lung Canc Res Programme, Liverpool, Merseyside, England. [Vineis, P] Univ Turin, Serv Epidemiol Tumori, Turin, Italy. [Vineis, P] CPO Piemonte, Turin, Italy. [Vineis, P, Riboli, E] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. [Clavel-Chapelon, F] E3N EPIC Grp Inst Gustave Roussy, INSERM, Villejuif, France. [Palli, D] Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, Florence, Italy. [Tumino, R] Azienda Osped Civile MP Arezzo, Canc Registry, Ragusa, Italy. [Tumino, R] Azienda Osped Civile MP Arezzo, Histopathol Unit, Ragusa, Italy. [Krogh, V] Fdn IRCCS, Ist Nazl Tumori, Milan, Italy. [Panico, S] Univ Naples Federico 2, Dipartimento Med Clin & Sperimentale, Naples, Italy. [Gonzalez, CA] ICO, RETICC DR06 0020, IDIBELL, Unit Nutr Environm & Canc, Barcelona, Spain. [Quiros, JR] Principado Asturias, Consejeria Serv Sociales, Jefe Secc Informac Sanitaria, Oviedo, Spain. [Martinez, C] Escuela Andaluza Salud Publ, Granada, Spain. [Navarro, C] Murcia Hlth Council, Dept Epidemiol, Murcia, Spain. [Ardanaz, E] Navarra Publ Hlth Inst, Pamplona, Spain. [Larranaga, N] Gobierno Vasco, Subdirecc Salud Publ Gipuzkoa, San Sebastian, Spain. [Khaw, KT] Univ Cambridge, Sch Clin Med, Cambridge, England. [Key, T] Univ Oxford, Canc Res UK, Oxford, England. [Bueno-de-Mesquita, HB] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Peeters, PHM] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. [Trichopoulou, A] Univ Athens Sch Med, WHO Collaborating Ctr Nutr, Dept Hyg Epidemiol & Med Stat, Athens, Greece. [Linseisen, J] Helmholtz Ctr Munich, Inst Epidemiol, Neuherberg, Germany. [Linseisen, J] German Canc Res Ctr, Div Clin Epidemiol, D-6900 Heidelberg, Germany. [Boeing, H] Deutsch Inst Ernahrungsforsch, Dept Epidemiol, Potsdam, Germany. [Hallmans, G] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Overvad, K] Aarhus Univ, Dept Epidemiol & Social Med, Aarhus, Denmark. Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Kumle, M] Univ Hosp No Norway, Tromso, Norway. [Valk, K, Voodern, T, Metspalu, A] Univ Tartu, EE-50090 Tartu, Estonia. [Zelenika, D, Boland, A, Delepine, M, Foglio, M, Lechner, D, Gut, IG, Heath, S, Lathrop, M] Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France. [Blanche, H, Lathrop, M] Fdn Jean Dausset CEPH, Paris, France. [Galan, P] Univ Paris 13, INSERM INRA CNAM U557 U1125, Bobigny, France. [Hayes, RB] New York Univ Langone Med Ctr, New York, NY USA, Support for the central Europe and ARCAGE genome-wide studies and follow-up genotyping was provided by INCa, France. Additional funding for study coordination, genotyping of replication studies, and statistical analysis was provided by the US NCI (R01 CA092039 05/05S1)., Norges teknisk-naturvitenskapelige universitet, Det medisinske fakultet, Institutt for samfunnsmedisin, McKay, J.D., Truong, T., Gaborieau, V., Chabrier, A., Chuang, S.-C., Byrnes, G., Zaridze, D., Shangina, O., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Bucur, A., Bencko, V., Holcatova, I., Janout, V., Foretova, L., Lagiou, P., Trichopoulos, D., Benhamou, S., Bouchardy, C., Ahrens, W., Merletti, F., Richiardi, L., Talamini, R., Barzan, L., Kjaerheim, K., Macfarlane, G.J., Macfarlane, T.V., Simonato, L., Canova, C., Agudo, A., Castellsagué, X., Lowry, R., Conway, D.I., McKinney, P.A., Healy, C.M., Toner, M.E., Znaor, A., Curado, M.P., Koifman, S., Menezes, A., Wünsch-Filho, V., Neto, J.E., Garrote, L.F., Boccia, S., Cadoni, G., Arzani, D., Olshan, A.F., Weissler, M.C., Funkhouser, W.K., Luo, J., Lubinski, J., Trubicka, J., Lener, M., Oszutowska, D., Schwartz, S.M., Chen, C., Fish, S., Doody, D.R., Muscat, J.E., Lazarus, P., Gallagher, C.J., Chang, S.-C., Zhang, Z.-F., Wei, Q., Sturgis, E.M., Wang, L.-E., Franceschi, S., Herrero, R., Kelsey, K.T., McClean, M.D., Marsit, C.J., Nelson, H.H., Romkes, M., Buch, S., Nukui, T., Zhong, S., Lacko, M., Manni, J.J., Peters, W.H.M., Hung, R.J., McLaughlin, J., Vatten, L., Njølstad, I., Goodman, G.E., Field, J.K., Liloglou, T., Vineis, P., Clavel-Chapelon, F., Palli, D., Tumino, R., Krogh, V., Panico, S., González, C.A., Quirós, J.R., Martínez, C., Navarro, C., Ardanaz, E., Larrañaga, N., Khaw, K.-T., Key, T., Bueno-de-Mesquita, H.B., Peeters, P.H.M., Trichopoulou, A., Linseisen, J., Boeing, H., Hallmans, G., Overvad, K., Tjønneland, A., Kumle, M., Riboli, E., Välk, K., Voodern, T., Metspalu, A., Zelenika, D., Boland, A., Delepine, M., Foglio, M., Lechner, D., Blanché, H., Gut, I.G., Galan, P., Heath, S., Hashibe, M., Hayes, R.B., Boffetta, P., Lathrop, M., Brennan, P., Promovendi PHPC, Metamedica, KNO, RS: MHeNs School for Mental Health and Neuroscience, and RS: GROW - School for Oncology and Reproduction

Subjects
Male, Cancer Research, Candidate gene, Linkage disequilibrium, [SDV]Life Sciences [q-bio], Genome-wide association study, FAMILY-HISTORY, genome-wide, Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Research Design::Genome-Wide Association Study [Medical Subject Headings], 0302 clinical medicine, Gene Frequency, NECK-CANCER, Risk Factors, Càncer, SUSCEPTIBILITY LOCUS, SENSITIVITY PROTEIN MUS308, Genetics (clinical), Cancer, Genetics & Heredity, Genetics, Publication Characteristics::Study Characteristics::Multicenter Study [Medical Subject Headings], 0303 health sciences, TOBACCO-RELATED CANCERS, Tumor, Continental Population Groups, Middle Aged, 3. Good health, LUNG-CANCER, POOLED ANALYSIS, EPIDEMIOLOGY CONSORTIUM, INTERNATIONAL HEAD, ALCOHOL-DRINKING, Head and Neck Neoplasms, Drinking of alcoholic beverages, 030220 oncology & carcinogenesis, NEOPLASIAS, Consum d'alcohol, Head and Neck Neoplasms/enzymology/epidemiology/genetics, Genetics and Genomics/Gene Discovery, Female, Settore MED/31 - OTORINOLARINGOIATRIA, Life Sciences & Biomedicine, Medical Genetics, Research Article, Adult, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714, Diseases::Neoplasms::Neoplasms by Site::Head and Neck Neoplasms [Medical Subject Headings], lcsh:QH426-470, Neoplasias de Cabeza y Cuello, VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical genetics: 714, Genetics and Genomics/Complex Traits, Biology, association study, Estudio de Asociación del Genoma Completo, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], 03 medical and health sciences, upper aerodigestive tract, Genetic variation, Biomarkers, Tumor, medicine, cancers, cancer, Humans, Genetic Predisposition to Disease, ddc:610, Tumor Markers, Biological/genetics, Genetics and Genomics/Cancer Genetics, Molecular Biology, Genotyping, Allele frequency, Settore MED/42 - IGIENE GENERALE E APPLICATA, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Genetic association, ddc:613, Aged, Medicinsk genetik, Estudio Multicéntrico, Science & Technology, Racial Groups, Genetic Variation, Aldehyde Dehydrogenase, medicine.disease, lcsh:Genetics, Aldehyde Dehydrogenase/genetics, Genome-Wide Association Study, Persons::Persons::Population Groups::Continental Population Groups [Medical Subject Headings], INHANCE consortium, sensitivity protein mus308, tobacco-related cancers, lung-cancer, pooled analysis, susceptibility locus, neck-cancer, epidemiology consortium, international head, alcohol-drinking, family-history, INHANCE Consortium, Biomarkers, Genètica
Abstract

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility., Author Summary We have used a two-phased study approach to identify common genetic variation involved in susceptibility to upper aero-digestive tract cancer. Using Illumina HumanHap300 beadchips, 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls, were genotyped for a panel 317,000 genetic variants that represent the majority of common genetic in the human genome. The 19 top-ranked variants were then studied in an additional series of 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies. Five variants were significantly associated with UADT cancer risk after the completion of both stages, including three residing within the alcohol dehydrogenase genes (ADH1B, ADH1C, ADH7) that have been previously described. Two additional variants were found, one near the ALDH2 gene and a second variant located in HEL308, a DNA repair gene. These results implicate two variants 4q21 and 12q24 and further highlight three ADH variants UADT cancer susceptibility.

Published
2011

26. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

Author

Anne Claude Tabet, Françoise Devillard, Christelle M. Durand, Dominique Bonneau, Caroline Schluth-Bolard, Hugo Peyre, Frédérique Amsellem, Jennifer L. Howe, Brigitte Assouline, Laurence Perrin, Patrick Edery, Gudrun A. Rappold, Alexis Brice, Tobias M. Boeckers, Kevin Mouzat, Mary Coleman, Diana Zelenika, Guy A. Rouleau, Christel Depienne, Alexandra Afenjar, Pilar Galan, Peter Szatmari, Coline Stordeur, Fabienne Giuliano, Thomas Bourgeron, Delphine Héron, Anthony P. Monaco, Aurélia Jacquette, Marion Leboyer, Elena Maestrini, Roberto Toro, Anne Polge, Serge Lumbroso, Richard Delorme, Maria Råstam, François Rivier, Richard Holt, Stephen W. Scherer, Jessica Guibert, Elodie Ey, Dalila Pinto, Christopher Gillberg, Béatrice Regnault, Fanny Laffargue, Claire S. Leblond, Julie Gauthier, Nathalie Lemière, James Lespinasse, Alexandre Mathieu, Michael J. Schmeisser, Jean Chiesa, Agnès Rastetter, Marc Delepine, Catalina Betancur, I. Carina Gillberg, Daisuke Sato, Mark Lathrop, Caroline Nava, Damien Sanlaville, Guillaume Huguet, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratoire de diagnotic moléculaire, CHU Sainte Justine [Montréal], Service de génétique médicale, Hôpital l'Archet, Service de Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Laboratoire de sciences cognitives et psycholinguistique (LSCP), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Fondation FondaMental [Créteil], Department of Clinical Sciences, Lund University [Lund], Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Department of Molecular Human Genetics, Universität Heidelberg [Heidelberg] = Heidelberg University, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Unité Pédopsychiatrique et Neuropédiatrique de Diagnostic et d'Evaluation des Troubles Envahissants du Développement, Centre Alpin de DIagnostic Précoce de l'Autisme - CADIPA-Centre Hospitalier Alpes Isère, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, Laboratoire de Cytogénétique, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie et Génétique, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génotypage des Eucaryotes (Plate-Forme), Institut Pasteur [Paris] (IP), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut for Anatomy and Cell Biology, Universität Ulm - Ulm University [Ulm, Allemagne], Foundation for Autism Research, Center of Excellence in Neuroscience, CHU de Montréal, Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Institute of Child Health, University College of London [London] (UCL), This work was funded by the Institut Pasteur, CNRS, INSERM, AP-HP, University Paris Diderot, the Bettencourt-Schueller foundation, the Orange foundation, the FondaMental foundation, the Conny-Maeva foundation, the Cognacq-Jay foundation, the ANR (ANR-08-MNPS-037-01 - SynGen), Neuron- ERANET (EUHF-AUTISM), the DFG (BO1718/3-1, 4-1) and Baustein L.SBN.0081., Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, Giuliano F, Stordeur C, Depienne C, Mouzat K, Pinto D, Howe J, Lemière N, Durand CM, Guibert J, Ey E, Toro R, Peyre H, Mathieu A, Amsellem F, Rastam M, Gillberg IC, Rappold GA, Holt R, Monaco AP, Maestrini E, Galan P, Heron D, Jacquette A, Afenjar A, Rastetter A, Brice A, Devillard F, Assouline B, Laffargue F, Lespinasse J, Chiesa J, Rivier F, Bonneau D, Regnault B, Zelenika D, Delepine M, Lathrop M, Sanlaville D, Schluth-Bolard C, Edery P, Perrin L, Tabet AC, Schmeisser MJ, Boeckers TM, Coleman M, Sato D, Szatmari P, Scherer SW, Rouleau GA, Betancur C, Leboyer M, Gillberg C, Delorme R, Bourgeron T, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg], University of Oxford [Oxford], Unité Fonctionnelle de Génétique Clinique [CHU Pitié Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris], Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), and Betancur, Catalina

Subjects
Male, Cancer Research, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, GENE DELETION, 0302 clinical medicine, Cognition, Intellectual disability, Child, Genetics (clinical), Genetics, Psychiatry, Neurons, 0303 health sciences, Mutation, SDV:GEN, META-ANALYSIS, Penetrance, Hypotonia, 3. Good health, SHANK2, Autism spectrum disorder, Female, medicine.symptom, Research Article, lcsh:QH426-470, DNA Copy Number Variations, Nerve Tissue Proteins, Biology, 03 medical and health sciences, Intellectual Disability, mental disorders, medicine, Humans, Clinical significance, AUTISM, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Biology and Life Sciences, Human Genetics, medicine.disease, lcsh:Genetics, Child Development Disorders, Pervasive, Case-Control Studies, Synapses, Autism, Cognition Disorders, 030217 neurology & neurosurgery
Abstract

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—warrant its consideration for mutation screening in clinical practice., Author Summary Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders. Mutations altering genes involved in the junction between brain cells have been repeatedly associated in ASD. For example, SHANK1, SHANK2 and SHANK3 emerged as one family of genes that are associated with ASD. However, little was known about the number of patients carrying these mutations and the clinical outcome. Here, we performed a new genetic screen of SHANK mutations and these results were analyzed in combination with those of the literature. In summary, SHANK mutations account for ∼1% of patients with ASD and were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. Given the high frequency and impact of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—this gene should be screened for mutations in clinical practice.

Published
2014

27. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders

Author

Christian Proepper, Dominique Bonneau, Catalina Betancur, Sarah Curran, Astrid M. Vicente, Henrik Anckarsäter, Elena Bacchelli, Sabine M. Klauck, Eftichia Duketis, Guiomar Oliveira, Fabien Fauchereau, Richard Delorme, Irma Järvelä, I. Carina Gillberg, Marina Konyukh, Stephen W. Scherer, Pauline Chaste, Elena Maestrini, Guillaume Huguet, Dalila Pinto, David Skuse, Marie-Christine Mouren, Béatrice Regnault, Nathalie Lemière, Jonas Melke, Christopher Gillberg, Bárbara Oliveira, Maria Råstam, Thomas Bourgeron, Marnie Kopp, Marc Delepine, Oriane Mercati, Raija Vanhala, Luigi Mazzone, Marion Leboyer, Richard Holt, Agatino Battaglia, Fiorella Minopoli, Katri Kantojärvi, Diana Zelenika, Liliana Ruta, Roberto Toro, Ana Filipa Sequeira, Françoise Devillard, Brigitte Assouline, Martin Poot, Elodie Ey, Regina Waltes, Vincent Guinchat, Tobias M. Boeckers, Jutta Heinrich, Anthony P. Monaco, Gudrun Nygren, Fritz Poustka, Mark Lathrop, David A. Collier, Claire S. Leblond, Patrick Bolton, Christine M. Freitag, Andreas G. Chiocchetti, Betancur, Catalina, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Universität Ulm - Ulm University [Ulm, Allemagne], Service de psychopathologie de l'enfant et de l'adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Child and Adolescent Psychiatry, University of Gothenburg (GU), Forensic Psychiatry, Lund University [Lund], Department of Pharmacology, Génotypage des Eucaryotes (Plate-Forme), Institut Pasteur [Paris] (IP), Behavioural and Brain Sciences Unit, Institute of Child Health, University College of London [London] (UCL), University Medical Center [Utrecht], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King‘s College London, Social, Genetic and Developmental Psychiatry Centre (SGDP), Institute of psychiatry, Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Institute of Biotechnology, Department of Psychiatry and Behavioral Sciences [Stanford], Stanford Medicine, Stanford University-Stanford University, Division of Child Neurology and Psychiatry, Department of Paediatrics, Università degli studi di Catania = University of Catania (Unict), Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Biologie Neurovasculaire Intégrée (BNVI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité Pédopsychiatrique et Neuropédiatrique de Diagnostic et d'Evaluation des Troubles Envahissants du Développement, Centre Alpin de DIagnostic Précoce de l'Autisme - CADIPA-Centre Hospitalier Alpes Isère, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institute for Anatomy and Cell Biology, Department of Medical and Clinical Genetics, Leblond C.S., Heinrich J., Delorme R., Proepper C., Betancur C., Huguet G., Konyukh M., Chaste P| Ey E., Rastam M., Anckarsäter H., Nygren G., Gillberg IC., Melke J., Toro R., Regnault B., Fauchereau F., Mercati O., Lemière N., Skuse D., Poot M., Holt R., Monaco A.P., Järvelä I., Kantojärvi K., Vanhala R., Curran S., Collier D.A., Bolton P., Chiocchetti A., Klauck S.M., Poustka F., Freitag C.M., Waltes R., Kopp M., Duketis E., Bacchelli E., Minopoli F., Ruta L., Battaglia A., Mazzone L., Maestrini E., Sequeira A.F., Oliveira B., Vicente A., Oliveira G., Pinto D., Scherer S.W., Zelenika D., Delepine M., Lathrop M., Bonneau D., Guinchat V., Devillard F., Assouline B., Mouren M.C., Leboyer M., Gillberg C., Boeckers T.M., Bourgeron T., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Anatomy and Cell Biology, Ulm University, University of Lund, Institut Pasteur [Paris], University of Oxford [Oxford], University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Università degli studi di Catania [Catania], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10

Subjects
Male, Gene Dosage, Receptors, Nicotinic, MESH: Protein Isoforms, HIDDEN-MARKOV MODEL, 0302 clinical medicine, MESH: Child, Protein Isoforms, Tissue Distribution, MESH: Nerve Tissue Proteins, Child, Neurons, 0303 health sciences, MESH: Alternative Splicing, PSYCHIATRIC-DISORDERS, CHRNA7, MESH: Sequence Deletion, 3. Good health, Autism spectrum disorder, Child, Preschool, Medicine, Adaptor Proteins, Signal Transducing, Adult, Alternative Splicing, Cell Line, Child Development Disorders, Pervasive, Female, Gene Expression Regulation, Humans, Nerve Tissue Proteins, RNA Splice Sites, Sequence Deletion, Synapses, alpha7 Nicotinic Acetylcholine Receptor, Child Development Disorders, education, COPY-NUMBER VARIATION, Molecular Genetics, 03 medical and health sciences, Genetics, AUTISM, MESH: Tissue Distribution, Molecular Biology, Biology, SNP GENOTYPING DATA, Ecology, Evolution, Behavior and Systematics, Pervasive, MESH: Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, RECURRENT MICRODELETIONS, MESH: Child, Preschool, Signal Transducing, MESH: Adult, SCAFFOLDING PROTEIN SHANK3, medicine.disease, Human genetics, MESH: Cell Line, MESH: Female, 030217 neurology & neurosurgery, Neuroscience, Cancer Research, MESH: Neurons, MESH: RNA Splice Sites, [SDV.GEN] Life Sciences [q-bio]/Genetics, Bioinformatics, Nicotinic, MESH: Child Development Disorders, Pervasive, MESH: Gene Dosage, MESH: Synapses, POSTSYNAPTIC DENSITY, Receptors, Copy-number variation, Genetics (clinical), Psychiatry, Adaptor Proteins, MESH: Gene Expression Regulation, Settore MED/39 - Neuropsichiatria Infantile, SHANK2, Mental Health, MESH: Receptors, Nicotinic, Research Article, lcsh:QH426-470, 15Q13.3 MICRODELETIONS, Genetic variation, mental disorders, medicine, ddc:610, Preschool, Gene, 030304 developmental biology, MESH: Male, lcsh:Genetics, DE-NOVO MUTATIONS, Perturbações do Desenvolvimento Infantil e Saúde Mental, biology.protein, Autism, 3111 Biomedicine, MENTAL-RETARDATION
Abstract

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23–4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11–q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the “multiple hit model” for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD., Author Summary Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While mutations in several genes have been identified in patients with ASD, little is known about their effects on neuronal function and their interaction with other genetic variations. Using a combination of genetic and functional approaches, we identified novel SHANK2 mutations including a de novo loss of one copy of the SHANK2 gene in a patient with autism and several mutations observed in patients that reduced neuronal cell contacts in vitro. Further genomic analysis of three patients carrying de novo SHANK2 deletions identified additional rare genomic imbalances previously associated with neuropsychiatric disorders. Taken together, these results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the “multiple hit model” for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

Published
2012

28. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25

Author

Lenka Foretova, Chu Chen, Eiliv Lund, Pierre Hainaut, Vladimir Bencko, Mario Foglio, Torgny Rasmuson, Wolfgang Ahrens, Vladimir Janout, Lars J. Vatten, George Xinarianos, Hans E. Krokan, Maiken Bratt Elvestad, Lorenzo Simonato, Paolo Vineis, Simon Heath, Adrian Cassidy, Fumihiko Matsuda, Françoise Clavel-Chapelon, Renato Talamini, Anne Boland, Peter Rudnai, Anush Mukeria, Gary J. Macfarlane, Marc Delepine, Franco Merletti, Doris Lechner, Ariana Znaor, Sheila Bingham, Diana Zelenika, Simone Benhamou, Gary E. Goodman, Geoffrey Liu, Hélène Blanché, Dana Mates, Claire M. Healy, Rayjean J. Hung, H. Bas Bueno-de-Mesquita, Neonilia Szeszenia-Dabrowska, Ivo Gut, John K. Field, David Zaridze, Jolanta Lissowska, Triantafillos Liloglou, Carmen Martinez, Frank Skorpen, Kristina Kjærheim, Dimitrios Trichopoulos, Ivana Holcatova, Kristian Hveem, Valerie Gaborieau, Paul Brennan, James McKay, Jakob Linseisen, Pagona Lagiou, Elio Riboli, Eleonora Fabianova, Mia Hashibe, John R. McLaughlin, Antonio Agudo, David I. Conway, Ray Lowry, Paolo Boffetta, Steven A. Narod, Mark Lathrop, School of Public Health, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Institute of Carcinogenesis, Russian Cancer Research Centre, Cancer Research Centre, Department of Epidemiology, Institute of Occupational Medicine, The M Sklodowska-Curie Cancer Center, Institute of Oncology, National Institute of Environment Health, Specialized Institute of Hygiene and Epidemiology, Regional Authority of Public Health-Specialized State Health Institute, Institute of Public Health, Institute of Hygiene and Epidemiology, Charles University [Prague] (CU)-1st Faculty of Medicine, Masaryk Memorial Cancer Institute (MMCI), Department of Preventive Medicine [Univ Palacký], Faculty of Medicine and Dentistry [Univ Palacký], Palacky University Olomouc-Palacky University Olomouc, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Roy Castle Lung Cancer Research Programme, University of Liverpool, University of Liverpool-Cancer Research Centre, Cancer Care Ontario, Samuel Lunenfeld Research Institute, Princess Margaret Hospital, Ontario Cancer Institute, Women's College Research Institute, University of Toronto, Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Division of Cancer Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Nutrition, hormones et cancer: épidémiologie et prévention (E3N), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Epidemiology and Public Health, Imperial College London, Centre for Nutrition and Health (CVG), National Institute for Public Health and the Environment [Bilthoven] (RIVM), Institute of Community Medicine, University of Tromsø (UiT), Andalusian School of Public Health [Granada], MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), Department of Radiation Sciences, Oncology, Umeå University, Bremen Institute for Prevention Research and Social Medicine, University of Bremen, INSERM U794, CEPH, Génomes et cancer (GC (FRE2939)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School [Athens], Harvard School of Public Health, Cancer Epidemiology Unit, Université de Turin, Cancer registry of Norway, University of Oslo (UiO), Institut Català d'Oncologia, Spain Institute of Oncology, University of Aberdeen, Aviano cancer center, Aviano Cancer Center, Department of Environmental Medicine and Public Health, Università degli Studi di Padova = University of Padua (Unipd), University of Newcastle Dental School, University of Newcastle, UK, University of Glasgow Dental School, University of Glasgow, Croatian National Cancer Registry, National Institute of Public Health, Trinity College School of Dental Science, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Hung, R.J., McKay, J.D., Gaborieau, V., Boffetta, P., Hashibe, M., Zaridze, D., Mukeria, A., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Mates, D., Bencko, V., Foretova, L., Janout, V., Chen, C., Goodman, G., Field, J.K., Liloglou, T., Xinarianos, G., Cassidy, A., McLaughlin, J., Liu, G., Narod, S., Krokan, H.E., Skorpen, F., Elvestad, M.B., Hveem, K., Vatten, L., Linseisen, J., Clavel-Chapelon, F., Vineis, P., Bueno-De-Mesquita, H.B., Lund, E., Martinez, C., Bingham, S., Rasmuson, T., Hainaut, P., Riboli, E., Ahrens, W., Benhamou, S., Lagiou, P., Trichopoulos, D., Holcátová, I., Merletti, F., Kjaerheim, K., Agudo, A., MacFarlane, G., Talamini, R., Simonato, L., Lowry, R., Conway, D.I., Znaor, A., Healy, C., Zelenika, D., Boland, A., Delepine, M., Foglio, M., Lechner, D., Matsuda, F., Blanche, H., Gut, I., Heath, S., Lathrop, M., Brennan, P., Savelli, Bruno, Masaryk Memorial Cancer Institute, Masaryk Memorial Cancer Institute (RECAMO), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), and Universita degli Studi di Padova

Subjects
Lung Neoplasms, Genotype, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Receptors, Nicotinic, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, ddc:610, nicotinic acetylcholine receptor, Lung cancer, 030304 developmental biology, Chromosomes, Human, Pair 15, 0303 health sciences, Multidisciplinary, CHRNA5, Respiratory disease, Cancer, medicine.disease, Lung cancer susceptibility, 3. Good health, Europe, Protein Subunits, lung cancer, Nicotinic acetylcholine receptor, Nicotinic agonist, 030220 oncology & carcinogenesis, Immunology, biology.protein
Abstract

Letter; International audience; Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually1. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 × 10$^{-10}$). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 × 10$^{-20}$ overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N′-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets

Published
2008

29. Correction to: Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities.

Author

Carmignac V, Mignot C, Blanchard E, Kuentz P, Aubriot-Lorton MH, Parker VER, Sorlin A, Fraitag S, Courcet JB, Duffourd Y, Rodriguez D, Knox RG, Polubothu S, Boland A, Olaso R, Delepine M, Darmency V, Riachi M, Quelin C, Rollier P, Goujon L, Grotto S, Capri Y, Jacquemont ML, Odent S, Amram D, Chevarin M, Vincent-Delorme C, Catteau B, Guibaud L, Arzimanoglou A, Keddar M, Sarret C, Callier P, Bessis D, Geneviève D, Deleuze JF, Thauvin C, Semple RK, Philippe C, Rivière JB, Kinsler VA, Faivre L, and Vabres P

Published
2021
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30. Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities.

Author

Carmignac V, Mignot C, Blanchard E, Kuentz P, Aubriot-Lorton MH, Parker VER, Sorlin A, Fraitag S, Courcet JB, Duffourd Y, Rodriguez D, Knox RG, Polubothu S, Boland A, Olaso R, Delepine M, Darmency V, Riachi M, Quelin C, Rollier P, Goujon L, Grotto S, Capri Y, Jacquemont ML, Odent S, Amram D, Chevarin M, Vincent-Delorme C, Catteau B, Guibaud L, Arzimanoglou A, Keddar M, Sarret C, Callier P, Bessis D, Geneviève D, Deleuze JF, Thauvin C, Semple RK, Philippe C, Rivière JB, Kinsler VA, Faivre L, and Vabres P

Subjects
Humans, Mechanistic Target of Rapamycin Complex 1 genetics, Mosaicism, Phenotype, TOR Serine-Threonine Kinases genetics, Hypopigmentation genetics, Megalencephaly
Abstract

Purpose: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI., Methods: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies., Results: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI., Conclusion: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex., (© 2021. The Author(s).)

Published
2021
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31. Genome sequencing in cytogenetics: Comparison of short-read and linked-read approaches for germline structural variant detection and characterization.

Author

Uguen K, Jubin C, Duffourd Y, Bardel C, Malan V, Dupont JM, El Khattabi L, Chatron N, Vitobello A, Rollat-Farnier PA, Baulard C, Lelorch M, Leduc A, Tisserant E, Tran Mau-Them F, Danjean V, Delepine M, Till M, Meyer V, Lyonnet S, Mosca-Boidron AL, Thevenon J, Faivre L, Thauvin-Robinet C, Schluth-Bolard C, Boland A, Olaso R, Callier P, Romana S, Deleuze JF, and Sanlaville D

Subjects
Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Chromosome Disorders diagnosis, Germ-Line Mutation, Humans, Intellectual Disability diagnosis, Intellectual Disability genetics, Chromosome Disorders genetics, Cytogenetics methods, Genetic Testing methods, Genomic Structural Variation, Whole Genome Sequencing methods
Abstract

Background: Structural variants (SVs) include copy number variants (CNVs) and apparently balanced chromosomal rearrangements (ABCRs). Genome sequencing (GS) enables SV detection at base-pair resolution, but the use of short-read sequencing is limited by repetitive sequences, and long-read approaches are not yet validated for diagnosis. Recently, 10X Genomics proposed Chromium, a technology providing linked-reads to reconstruct long DNA fragments and which could represent a good alternative. No study has compared short-read to linked-read technologies to detect SVs in a constitutional diagnostic setting yet. The aim of this work was to determine whether the 10X Genomics technology enables better detection and comprehension of SVs than short-read WGS., Methods: We included 13 patients carrying various SVs. Whole genome analyses were performed using paired-end HiSeq X sequencing with (linked-read strategy) or without (short-read strategy) Chromium library preparation. Two different bioinformatic pipelines were used: Variants are called using BreakDancer for short-read strategy and LongRanger for long-read strategy. Variant interpretations were first blinded., Results: The short-read strategy allowed diagnosis of known SV in 10/13 patients. After unblinding, the linked-read strategy identified 10/13 SVs, including one (patient 7) missed by the short-read strategy., Conclusion: In conclusion, regarding the results of this study, 10X Genomics solution did not improve the detection and characterization of SV., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Published
2020
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32. Variations of SOST mRNA expression in human bone are associated with DNA polymorphism and DNA methylation in the SOST gene.

Author

Lhaneche L, Hald JD, Domingues A, Hannouche D, Delepine M, Zelenika D, Boland A, Ostertag A, Cohen-Solal M, Langdahl BL, Harsløf T, de Vernejoul MC, Geoffroy V, and Jehan F

Subjects
Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Aged, 80 and over, Bone Morphogenetic Proteins biosynthesis, Cohort Studies, Female, Fractures, Bone genetics, Fractures, Bone metabolism, Gene Expression, Humans, Male, Middle Aged, Osteogenesis Imperfecta genetics, Osteogenesis Imperfecta metabolism, RNA, Messenger biosynthesis, Young Adult, Bone Density genetics, Bone Morphogenetic Proteins genetics, DNA Methylation genetics, Genetic Markers genetics, Genetic Variation genetics, Polymorphism, Genetic genetics, RNA, Messenger genetics
Abstract

SOST encodes sclerostin, an inhibitor of bone formation that antagonizes canonical Wnt signaling. Variations of SOST expression have an impact on bone mineral density (BMD) and bone strength. We hypothesized that genetic and epigenetic DNA modifications have an impact on SOST gene expression. By analyzing 43 bone samples from women, we found that rs851054 (G/A) is associated with SOST mRNA expression, donors with one or two G allele(s) displaying higher SOST expression (p<0.05). Beside this polymorphism, we also investigated the role of CpG methylation in SOST mRNA expression, and analyzed methylation variation at 13 CpG sites on the 1st exon of SOST in 14 human bone samples. Principal component analysis identified three groups of CpG sites that explained most of the methylation variation. We calculated the percentage of methylation in the main group of CpGs, and showed that higher rates of methylated CpGs are associated with higher SOST mRNA expression. To demonstrate that change in SOST expression might be related to human bone disease, we analyzed 131 patients with osteogenesis imperfecta (OI), a rare disease characterized by low BMD, bone fragility, and marked intra-familial variability of bone phenotypes. We found an association between rs851054 of the SOST promoter and the fracture rate only during childhood (p<0.01). In conclusion, genetic and epigenetic changes contribute to variation in SOST expression in human bone. Our data also indicate that these variations may be related to the severity of OI., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Published
2016
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33. Deep sequencing of the Trypanosoma cruzi GP63 surface proteases reveals diversity and diversifying selection among chronic and congenital Chagas disease patients.

Author

Llewellyn MS, Messenger LA, Luquetti AO, Garcia L, Torrico F, Tavares SB, Cheaib B, Derome N, Delepine M, Baulard C, Deleuze JF, Sauer S, and Miles MA

Subjects
Animals, Bolivia, Brazil, Chagas Disease congenital, Chronic Disease, Cohort Studies, Female, Gene Expression Regulation, Genotype, High-Throughput Nucleotide Sequencing, Humans, Infant, Infectious Disease Transmission, Vertical, Male, Peptide Hydrolases genetics, Protozoan Proteins genetics, Protozoan Proteins metabolism, Trypanosoma cruzi genetics, Trypanosoma cruzi metabolism, Chagas Disease parasitology, Genetic Variation, Peptide Hydrolases metabolism, Trypanosoma cruzi enzymology
Abstract

Background: Chagas disease results from infection with the diploid protozoan parasite Trypanosoma cruzi. T. cruzi is highly genetically diverse, and multiclonal infections in individual hosts are common, but little studied. In this study, we explore T. cruzi infection multiclonality in the context of age, sex and clinical profile among a cohort of chronic patients, as well as paired congenital cases from Cochabamba, Bolivia and Goias, Brazil using amplicon deep sequencing technology., Methodology/ Principal Findings: A 450bp fragment of the trypomastigote TcGP63I surface protease gene was amplified and sequenced across 70 chronic and 22 congenital cases on the Illumina MiSeq platform. In addition, a second, mitochondrial target--ND5--was sequenced across the same cohort of cases. Several million reads were generated, and sequencing read depths were normalized within patient cohorts (Goias chronic, n = 43, Goias congenital n = 2, Bolivia chronic, n = 27; Bolivia congenital, n = 20), Among chronic cases, analyses of variance indicated no clear correlation between intra-host sequence diversity and age, sex or symptoms, while principal coordinate analyses showed no clustering by symptoms between patients. Between congenital pairs, we found evidence for the transmission of multiple sequence types from mother to infant, as well as widespread instances of novel genotypes in infants. Finally, non-synonymous to synonymous (dn:ds) nucleotide substitution ratios among sequences of TcGP63Ia and TcGP63Ib subfamilies within each cohort provided powerful evidence of strong diversifying selection at this locus., Conclusions/significance: Our results shed light on the diversity of parasite DTUs within each patient, as well as the extent to which parasite strains pass between mother and foetus in congenital cases. Although we were unable to find any evidence that parasite diversity accumulates with age in our study cohorts, putative diversifying selection within members of the TcGP63I gene family suggests a link between genetic diversity within this gene family and survival in the mammalian host.

Published
2015
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34. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.

Author

Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, Giuliano F, Stordeur C, Depienne C, Mouzat K, Pinto D, Howe J, Lemière N, Durand CM, Guibert J, Ey E, Toro R, Peyre H, Mathieu A, Amsellem F, Rastam M, Gillberg IC, Rappold GA, Holt R, Monaco AP, Maestrini E, Galan P, Heron D, Jacquette A, Afenjar A, Rastetter A, Brice A, Devillard F, Assouline B, Laffargue F, Lespinasse J, Chiesa J, Rivier F, Bonneau D, Regnault B, Zelenika D, Delepine M, Lathrop M, Sanlaville D, Schluth-Bolard C, Edery P, Perrin L, Tabet AC, Schmeisser MJ, Boeckers TM, Coleman M, Sato D, Szatmari P, Scherer SW, Rouleau GA, Betancur C, Leboyer M, Gillberg C, Delorme R, and Bourgeron T

Subjects
Case-Control Studies, Child, Cognition physiology, DNA Copy Number Variations genetics, Female, Humans, Intellectual Disability genetics, Male, Neurons physiology, Synapses genetics, Child Development Disorders, Pervasive genetics, Cognition Disorders genetics, Mutation genetics, Nerve Tissue Proteins genetics
Abstract

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.

Published
2014
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35. AP1S2 is mutated in X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome).

Author

Cacciagli P, Desvignes JP, Girard N, Delepine M, Zelenika D, Lathrop M, Lévy N, Ledbetter DH, Dobyns WB, and Villard L

Subjects
Adolescent, Adult, Amino Acid Sequence, Basal Ganglia Diseases diagnosis, Child, Chromosomes, Human, X genetics, Dandy-Walker Syndrome diagnosis, Exome, Humans, Male, Mental Retardation, X-Linked diagnosis, Molecular Sequence Data, Pedigree, Polymorphism, Single Nucleotide, Seizures diagnosis, Adaptor Protein Complex sigma Subunits genetics, Basal Ganglia Diseases genetics, Dandy-Walker Syndrome genetics, Mental Retardation, X-Linked genetics, Mutation, Seizures genetics
Abstract

MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy-Walker malformation and inconstant choreoathetosis. Four individuals had iron deposition in the basal ganglia seen on MRI or at autopsy. The mutation causing Pettigrew has remained elusive since the initial description of the condition. We report the identification of a mutation in the X-linked AP1S2 gene in the original Pettigrew syndrome family using X-chromosome exome sequencing. We report additional phenotype details for several of the affected individuals, allowing us to further refine the phenotype corresponding to this X-linked intellectual disability syndrome. The AP1S2 c.426+1 G>T mutation segregates with the disease in the Pettigrew syndrome family and results in loss of 46 amino acids in the clathrin adaptor complex small chain domain that spans most of the AP1S2 protein sequence. The mutation reported here in AP1S2 is the first mutation that is not predicted to cause a premature termination of the coding sequence or absence of the AP1S2 protein. Although most of the families affected by a mutation in AP1S2 were initially described as having different disorders assigned to at least three different OMIM numbers (MIM 300629, 300630 and 304340), our analysis of the phenotype shows that they are all the same syndrome with recognition complicated by highly variable expressivity that is seen within as well as between families and is probably not explained by differences in mutation severity.

Published
2014
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36. Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus.

Author

Cacciagli P, Sutera-Sardo J, Borges-Correia A, Roux JC, Dorboz I, Desvignes JP, Badens C, Delepine M, Lathrop M, Cau P, Lévy N, Girard N, Sarda P, Boespflug-Tanguy O, and Villard L

Subjects
Cell Shape, Child, Child, Preschool, Deafness complications, Dystonia complications, Female, Fibroblasts pathology, Fibroblasts ultrastructure, Genetic Predisposition to Disease, Golgi Apparatus ultrastructure, Humans, Infant, Male, Myelin Sheath ultrastructure, Pedigree, Phenotype, Young Adult, Deafness genetics, Dystonia genetics, Genetic Diseases, X-Linked genetics, Golgi Apparatus pathology, Membrane Proteins genetics, Mutation genetics, Myelin Sheath pathology
Abstract

BAP31 is one of the most abundant endoplasmic reticulum (ER) membrane proteins. It is a chaperone protein involved in several pathways, including ER-associated degradation, export of ER proteins to the Golgi apparatus, and programmed cell death. BAP31 is encoded by BCAP31, located in human Xq28 and highly expressed in neurons. We identified loss-of-function mutations in BCAP31 in seven individuals from three families. These persons suffered from motor and intellectual disabilities, dystonia, sensorineural deafness, and white-matter changes, which together define an X-linked syndrome. In the primary fibroblasts of affected individuals, we found that BCAP31 deficiency altered ER morphology and caused a disorganization of the Golgi apparatus in a significant proportion of cells. Contrary to what has been described with transient-RNA-interference experiments, we demonstrate that constitutive BCAP31 deficiency does not activate the unfolded protein response or cell-death effectors. Rather, our data demonstrate that the lack of BAP31 disturbs ER metabolism and impacts the Golgi apparatus, highlighting an important role for BAP31 in ER-to-Golgi crosstalk. These findings provide a molecular basis for a Mendelian syndrome and link intracellular protein trafficking to severe congenital brain dysfunction and deafness., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2013
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37. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.

Author

Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G, Konyukh M, Chaste P, Ey E, Rastam M, Anckarsäter H, Nygren G, Gillberg IC, Melke J, Toro R, Regnault B, Fauchereau F, Mercati O, Lemière N, Skuse D, Poot M, Holt R, Monaco AP, Järvelä I, Kantojärvi K, Vanhala R, Curran S, Collier DA, Bolton P, Chiocchetti A, Klauck SM, Poustka F, Freitag CM, Waltes R, Kopp M, Duketis E, Bacchelli E, Minopoli F, Ruta L, Battaglia A, Mazzone L, Maestrini E, Sequeira AF, Oliveira B, Vicente A, Oliveira G, Pinto D, Scherer SW, Zelenika D, Delepine M, Lathrop M, Bonneau D, Guinchat V, Devillard F, Assouline B, Mouren MC, Leboyer M, Gillberg C, Boeckers TM, and Bourgeron T

Subjects
Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Adult, Alternative Splicing genetics, Cell Line, Child, Child, Preschool, Female, Gene Dosage genetics, Gene Expression Regulation, Humans, Male, Neurons cytology, Protein Isoforms genetics, Protein Isoforms metabolism, RNA Splice Sites genetics, Receptors, Nicotinic genetics, Receptors, Nicotinic metabolism, Synapses pathology, Tissue Distribution, alpha7 Nicotinic Acetylcholine Receptor, Child Development Disorders, Pervasive genetics, Nerve Tissue Proteins genetics, Sequence Deletion genetics, Synapses genetics
Abstract

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD., Competing Interests: The authors have declared that no competing interests exist.

Published
2012
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38. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

Author

Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Beaumont H, Warden D, Wilcock G, Love S, Kehoe PG, Hooper NM, Vardy ER, Hardy J, Mead S, Fox NC, Rossor M, Collinge J, Maier W, Jessen F, Rüther E, Schürmann B, Heun R, Kölsch H, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Gallacher J, Hüll M, Rujescu D, Giegling I, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, van Duijn CM, Breteler MM, Ikram MA, DeStefano AL, Fitzpatrick AL, Lopez O, Launer LJ, Seshadri S, Berr C, Campion D, Epelbaum J, Dartigues JF, Tzourio C, Alpérovitch A, Lathrop M, Feulner TM, Friedrich P, Riehle C, Krawczak M, Schreiber S, Mayhaus M, Nicolhaus S, Wagenpfeil S, Steinberg S, Stefansson H, Stefansson K, Snaedal J, Björnsson S, Jonsson PV, Chouraki V, Genier-Boley B, Hiltunen M, Soininen H, Combarros O, Zelenika D, Delepine M, Bullido MJ, Pasquier F, Mateo I, Frank-Garcia A, Porcellini E, Hanon O, Coto E, Alvarez V, Bosco P, Siciliano G, Mancuso M, Panza F, Solfrizzi V, Nacmias B, Sorbi S, Bossù P, Piccardi P, Arosio B, Annoni G, Seripa D, Pilotto A, Scarpini E, Galimberti D, Brice A, Hannequin D, Licastro F, Jones L, Holmans PA, Jonsson T, Riemenschneider M, Morgan K, Younkin SG, Owen MJ, O'Donovan M, Amouyel P, and Williams J

Subjects
Aged, Aged, 80 and over, Case-Control Studies, Databases, Genetic, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Multigene Family, Polymorphism, Single Nucleotide, Sialic Acid Binding Ig-like Lectin 3, ATP-Binding Cassette Transporters genetics, Adaptor Proteins, Signal Transducing genetics, Alzheimer Disease genetics, Antigens, CD genetics, Antigens, Differentiation, Myelomonocytic genetics, Cytoskeletal Proteins genetics, Membrane Proteins genetics, Receptor, EphA1 genetics
Abstract

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

Published
2011
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39. Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations.

Author

Lambert JC, Zelenika D, Hiltunen M, Chouraki V, Combarros O, Bullido MJ, Tognoni G, Fiévet N, Boland A, Arosio B, Coto E, Del Zompo M, Mateo I, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Delepine M, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Ravaglia G, Valdivieso F, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Licastro F, Lathrop M, Soininen H, and Amouyel P

Subjects
Finland, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Italy, Polymorphism, Single Nucleotide, Spain, White People genetics, Adaptor Proteins, Signal Transducing genetics, Alzheimer Disease genetics, Monomeric Clathrin Assembly Proteins genetics, Nuclear Proteins genetics, Tumor Suppressor Proteins genetics
Abstract

Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimer's disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [CI] [1.15-1.38], p = 2.9 × 10(-7), and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 × 10(-7), respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI [1.06-1.32], p = 2.0 × 10(-3)). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Published
2011
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40. A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.

Author

McKay JD, Truong T, Gaborieau V, Chabrier A, Chuang SC, Byrnes G, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Bucur A, Bencko V, Holcatova I, Janout V, Foretova L, Lagiou P, Trichopoulos D, Benhamou S, Bouchardy C, Ahrens W, Merletti F, Richiardi L, Talamini R, Barzan L, Kjaerheim K, Macfarlane GJ, Macfarlane TV, Simonato L, Canova C, Agudo A, Castellsagué X, Lowry R, Conway DI, McKinney PA, Healy CM, Toner ME, Znaor A, Curado MP, Koifman S, Menezes A, Wünsch-Filho V, Neto JE, Garrote LF, Boccia S, Cadoni G, Arzani D, Olshan AF, Weissler MC, Funkhouser WK, Luo J, Lubiński J, Trubicka J, Lener M, Oszutowska D, Schwartz SM, Chen C, Fish S, Doody DR, Muscat JE, Lazarus P, Gallagher CJ, Chang SC, Zhang ZF, Wei Q, Sturgis EM, Wang LE, Franceschi S, Herrero R, Kelsey KT, McClean MD, Marsit CJ, Nelson HH, Romkes M, Buch S, Nukui T, Zhong S, Lacko M, Manni JJ, Peters WH, Hung RJ, McLaughlin J, Vatten L, Njølstad I, Goodman GE, Field JK, Liloglou T, Vineis P, Clavel-Chapelon F, Palli D, Tumino R, Krogh V, Panico S, González CA, Quirós JR, Martínez C, Navarro C, Ardanaz E, Larrañaga N, Khaw KT, Key T, Bueno-de-Mesquita HB, Peeters PH, Trichopoulou A, Linseisen J, Boeing H, Hallmans G, Overvad K, Tjønneland A, Kumle M, Riboli E, Välk K, Vooder T, Metspalu A, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Blanché H, Gut IG, Galan P, Heath S, Hashibe M, Hayes RB, Boffetta P, Lathrop M, and Brennan P

Subjects
Adult, Aged, Aldehyde Dehydrogenase genetics, Biomarkers, Tumor genetics, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Head and Neck Neoplasms enzymology, Head and Neck Neoplasms epidemiology, Humans, Male, Middle Aged, Racial Groups, Risk Factors, Genome-Wide Association Study, Head and Neck Neoplasms genetics
Abstract

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10⁻⁸) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸); rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility., Competing Interests: The authors have declared that no competing interests exist.

Published
2011
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41. Systematic analysis of candidate genes for Alzheimer's disease in a French, genome-wide association study.

Author

Laumet G, Chouraki V, Grenier-Boley B, Legry V, Heath S, Zelenika D, Fievet N, Hannequin D, Delepine M, Pasquier F, Hanon O, Brice A, Epelbaum J, Berr C, Dartigues JF, Tzourio C, Campion D, Lathrop M, Bertram L, Amouyel P, and Lambert JC

Subjects
Aged, Aged, 80 and over, Alzheimer Disease psychology, DNA genetics, Databases, Genetic, Female, France, Gene Frequency, Genetic Markers, Genome-Wide Association Study, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Psychiatric Status Rating Scales, Alzheimer Disease genetics
Abstract

We selected twenty genes from the "Top Results" list on the AlzGene database website and assessed their association with risk of developing Alzheimer's disease (AD) in a large, genome-wide association study (using 526 SNPs from 2,032 AD cases and 5,328 controls) performed in France. The APOE, CLU, PICALM, and CR1 loci were excluded, since they had already been extensively analyzed. Ten genes/loci (TFAM, SORL1, CHRNB2, SORCS1, DAPK1, MTHFR, GWA 14q32.13, BDNF, NEDD9, and CH25H) showed weak nominal association with AD risk, in line with previous studies. In the remaining ten genes/loci (TNK1, ACE, CST3, IL1B, hCG2039140, PRNP, GAB2, LOC651924, IL1A, and TF), no single nucleotide polymorphisms were associated in our dataset. Of the genes showing nominal association in our cohorts, TFAM and CHRNB2 appear particularly interesting and warrant further genetic and functional follow-up analyses.

Published
2010
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42. The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study.

Author

Lambert JC, Sleegers K, González-Pérez A, Ingelsson M, Beecham GW, Hiltunen M, Combarros O, Bullido MJ, Brouwers N, Bettens K, Berr C, Pasquier F, Richard F, Dekosky ST, Hannequin D, Haines JL, Tognoni G, Fiévet N, Dartigues JF, Tzourio C, Engelborghs S, Arosio B, Coto E, De Deyn P, Del Zompo M, Mateo I, Boada M, Antunez C, Lopez-Arrieta J, Epelbaum J, Schjeide BM, Frank-Garcia A, Giedraitis V, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Delepine M, Zelenika D, Lathrop M, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Ravaglia G, Valdivieso F, Vepsäläinen S, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Hanon O, Piccardi P, Annoni G, Mann D, Marambaud P, Seripa D, Galimberti D, Tanzi RE, Bertram L, Lendon C, Lannfelt L, Licastro F, Campion D, Pericak-Vance MA, Soininen H, Van Broeckhoven C, Alpérovitch A, Ruiz A, Kamboh MI, and Amouyel P

Subjects
Age of Onset, Aged, Aged, 80 and over, Alleles, Apolipoprotein E4 genetics, Apolipoprotein E4 metabolism, Calcium Channels metabolism, Case-Control Studies, Female, Humans, Male, Membrane Glycoproteins metabolism, Middle Aged, Alzheimer Disease epidemiology, Alzheimer Disease genetics, Calcium Channels genetics, Membrane Glycoproteins genetics, Polymorphism, Genetic genetics
Abstract

The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the ε4 allele of the APOE gene.

Published
2010
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43. Lung cancer susceptibility locus at 5p15.33.

Author

McKay JD, Hung RJ, Gaborieau V, Boffetta P, Chabrier A, Byrnes G, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, McLaughlin J, Shepherd F, Montpetit A, Narod S, Krokan HE, Skorpen F, Elvestad MB, Vatten L, Njølstad I, Axelsson T, Chen C, Goodman G, Barnett M, Loomis MM, Lubiñski J, Matyjasik J, Lener M, Oszutowska D, Field J, Liloglou T, Xinarianos G, Cassidy A, Vineis P, Clavel-Chapelon F, Palli D, Tumino R, Krogh V, Panico S, González CA, Ramón Quirós J, Martínez C, Navarro C, Ardanaz E, Larrañaga N, Kham KT, Key T, Bueno-de-Mesquita HB, Peeters PH, Trichopoulou A, Linseisen J, Boeing H, Hallmans G, Overvad K, Tjønneland A, Kumle M, Riboli E, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, and Brennan P

Subjects
Apoptosis, Case-Control Studies, Genome-Wide Association Study, Humans, Principal Component Analysis, Smoking, Chromosomes, Human, Pair 5 genetics, Genetic Predisposition to Disease, Lung Neoplasms genetics, Membrane Proteins genetics, Neoplasm Proteins genetics, Telomerase genetics
Abstract

We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.

Published
2008
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44. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.

Author

Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Chen C, Goodman G, Field JK, Liloglou T, Xinarianos G, Cassidy A, McLaughlin J, Liu G, Narod S, Krokan HE, Skorpen F, Elvestad MB, Hveem K, Vatten L, Linseisen J, Clavel-Chapelon F, Vineis P, Bueno-de-Mesquita HB, Lund E, Martinez C, Bingham S, Rasmuson T, Hainaut P, Riboli E, Ahrens W, Benhamou S, Lagiou P, Trichopoulos D, Holcátová I, Merletti F, Kjaerheim K, Agudo A, Macfarlane G, Talamini R, Simonato L, Lowry R, Conway DI, Znaor A, Healy C, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, and Brennan P

Subjects
Europe, Genotype, Humans, Odds Ratio, Polymorphism, Single Nucleotide genetics, Chromosomes, Human, Pair 15 genetics, Genetic Predisposition to Disease genetics, Lung Neoplasms genetics, Protein Subunits genetics, Receptors, Nicotinic genetics
Abstract

Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.

Published
2008
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45. SRPX2 mutations in disorders of language cortex and cognition.

Author

Roll P, Rudolf G, Pereira S, Royer B, Scheffer IE, Massacrier A, Valenti MP, Roeckel-Trevisiol N, Jamali S, Beclin C, Seegmuller C, Metz-Lutz MN, Lemainque A, Delepine M, Caloustian C, de Saint Martin A, Bruneau N, Depétris D, Mattéi MG, Flori E, Robaglia-Schlupp A, Lévy N, Neubauer BA, Ravid R, Marescaux C, Berkovic SF, Hirsch E, Lathrop M, Cau P, and Szepetowski P

Subjects
Adult, Amino Acid Sequence, Animals, Apraxias genetics, Apraxias metabolism, Base Sequence, CHO Cells, Child, Child, Preschool, Cricetinae, Epilepsy, Rolandic genetics, Epilepsy, Rolandic metabolism, Female, Fibroblasts metabolism, Genetic Linkage, Genetic Testing, Glycosylation, Humans, Immunohistochemistry, Intellectual Disability metabolism, Language Disorders metabolism, Language Disorders physiopathology, Male, Membrane Proteins metabolism, Mice, Molecular Sequence Data, Neoplasm Proteins, Nerve Tissue Proteins metabolism, Transfection, Cerebral Cortex metabolism, Cognition, Language Disorders genetics, Membrane Proteins genetics, Mutation, Nerve Tissue Proteins genetics
Abstract

The rolandic and sylvian fissures divide the human cerebral hemispheres and the adjacent areas participate in speech processing. The relationship of rolandic (sylvian) seizure disorders with speech and cognitive impairments is well known, albeit poorly understood. We have identified the Xq22 gene SRPX2 as being responsible for rolandic seizures (RSs) associated with oral and speech dyspraxia and mental retardation (MR). SRPX2 is a secreted sushi-repeat containing protein expressed in neurons of the human adult brain, including the rolandic area. The disease-causing mutation (N327S) resulted in gain-of-glycosylation of the secreted mutant protein. A second mutation (Y72S) was identified within the first sushi domain of SRPX2 in a male with RSs and bilateral perisylvian polymicrogyria and his female relatives with mild MR or unaffected carrier status. In cultured cells, both mutations were associated with altered patterns of intracellular processing, suggesting protein misfolding. In the murine brain, Srpx2 protein expression appeared in neurons at birth. The involvement of SRPX2 in these disorders suggests an important role for SRPX2 in the perisylvian region critical for language and cognitive development.

Published
2006
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46. The origin of a developmentally regulated Igh replicon is located near the border of regulatory domains for Igh replication and expression.

Author

Zhou J, Ashouian N, Delepine M, Matsuda F, Chevillard C, Riblet R, Schildkraut CL, and Birshtein BK

Subjects
Animals, CCAAT-Enhancer-Binding Protein-beta genetics, Carrier Proteins genetics, Cell Line, Chromosomes, Artificial, Bacterial genetics, DNA Replication genetics, Expressed Sequence Tags, Gene Expression Regulation, Immunoglobulin A genetics, LIM Domain Proteins, Mice, Molecular Sequence Data, Multigene Family, Proteins genetics, Replication Origin, Trans-Activators, Histone Deacetylases, Immunoglobulin Heavy Chains genetics, Replicon genetics, Repressor Proteins
Abstract

The 3' Ig heavy chain locus (Igh) regulatory region is the most downstream known element of the murine Igh gene cluster. We report here that the nearest non-Igh genes-Crip, Crp2, and Mta1-are located approximately 70 kb further downstream and are beyond the end of the domain of Igh transcriptional regulation. We have localized an origin of replication in MEL cells to a 3-kb segment located between the 3' Igh regulatory region and Crip. Sequences downstream of this origin are replicated by forks that move in both directions. Sequences upstream of this origin (Igh-C, -D, and -J) are replicated in a single direction through a 500-kb segment in which no active bidirectional origins can be detected. We propose that this origin may lie at or near the end of the Igh regulation domain.

Published
2002
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47. Genetic analysis of chromosome 2 in type 1 diabetes: analysis of putative loci IDDM7, IDDM12, and IDDM13 and candidate genes NRAMP1 and IA-2 and the interleukin-1 gene cluster. IMDIAB Group.

Author

Esposito L, Hill NJ, Pritchard LE, Cucca F, Muxworthy C, Merriman ME, Wilson A, Julier C, Delepine M, Tuomilehto J, Tuomilehto-Wolf E, Ionesco-Tirgoviste C, Nistico' L, Buzzetti R, Pozzilli P, Ferrari M, Bosi E, Pociot F, Nerup J, Bain SC, and Todd JA

Subjects
Denmark, Finland, France, Genetic Linkage, Humans, Italy, Microsatellite Repeats, Romania, United Kingdom, United States, Chromosomes, Human, Pair 2, Diabetes Mellitus, Type 1 genetics, Interleukin-1 genetics, Multigene Family
Published
1998
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48. Multiple DNA variant association analysis: application to the insulin gene region in type I diabetes.

Author

Julier C, Lucassen A, Villedieu P, Delepine M, Levy-Marchal C, Danzé PM, Bianchi F, Boitard C, Froguel P, and Bell J

Subjects
Diabetes Mellitus, Type 1 epidemiology, Disease Susceptibility, France epidemiology, Humans, Diabetes Mellitus, Type 1 genetics, Genetic Variation, Insulin genetics, Molecular Epidemiology methods
Abstract

Association and linkage studies have shown that at least one of the genetic factors involved in susceptibility to insulin-dependent diabetes mellitus (IDDM) is contained within a 4.1-kb region of the insulin gene. Sequence analysis has led to the identification of 10 DNA variants in this region that are associated with increased risk for IDDM. These variants are in strong linkage disequilibrium with each other, and previous studies have failed to distinguish between the variant(s) that cause increased susceptibility to IDDM and others that are associated with the disease because of linkage disequilibrium. To address this problem, we have undertaken a large population study of French diabetics and controls and have analyzed genotype patterns for several of the variant sites simultaneously. This has led to the identification of a subset consisting of four variants (-2733AC, -23HphI, -365VNTR, and +1140AC), at least one of which appears to be directly implicated in disease susceptibility. The multiple-DNA-variant association-analysis approach that is applied here to the problem of identifying potential susceptibility variants in IDDM is likely to be important in studies of many other multifactorial diseases.

Published
1994

49. Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q.

Author

Hashimoto L, Habita C, Beressi JP, Delepine M, Besse C, Cambon-Thomsen A, Deschamps I, Rotter JI, Djoulah S, and James MR

Subjects
Chromosome Mapping, Chromosomes, Human, Pair 8, Genetic Linkage, Genetic Markers, Genetic Predisposition to Disease, Humans, Major Histocompatibility Complex, Chromosomes, Human, Pair 11, Diabetes Mellitus, Type 1 genetics
Abstract

Loci in the major histocompatibility complex (MHC) on chromosome 6 and the insulin (INS) region on chromosome 11 have been implicated in susceptibility to insulin-dependent diabetes mellitus (IDDM) through candidate gene investigations, but they may account for less than 50% of genetic risk for the disease. Genome-wide linkage studies have led to localization of more than 10 susceptibility loci for insulin-dependent diabetes in the non-obese diabetic (NOD) mouse and the BB rat. Similar studies are now possible in humans through the development of dense genetic maps of highly informative microsatellite loci obtained using polymerase chain reaction analysis. We have applied microsatellite markers from recent Généthon maps, and other highly informative markers, in a genome-wide linkage study in IDDM. Here we report evidence for the localization of a previously undetected susceptibility locus for IDDM in the region of the FGF3 gene on chromosome 11q. Our results shows the potential of genome-wide linkage studies to detect susceptibility loci in IDDM and other multifactorial disorders.

Published
1994
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