Professor Lefkos Middleton

Vilarino-Guell C, Soto AI, Lincoln SJ, Ben Yahmed S, Kefi M, Heckman MG, Hulihan MM, Chai H, Diehl NN, Amouri R, Rajput A, Mash DC, Dickson DW, Middleton LT, Gibson RA, Hentati F, Farrer MJet al., 2009, <i>ATP13A2</i> Variability in Parkinson Disease, HUMAN MUTATION, Vol: 30, Pages: 406-410, ISSN: 1059-7794

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• Citations: 33

Need AC, Ge D, Weale ME, Maia J, Feng S, Heinzen EL, Shianna KV, Yoon W, Kasperaviciute D, Gennarelli M, Strittmatter WJ, Bonvicini C, Rossi G, Jayathilake K, Cola PA, McEvoy JP, Keefe RSE, Fisher EMC, St Jean PL, Giegling I, Hartmann AM, Moeller H-J, Ruppert A, Fraser G, Crombie C, Middleton LT, St Clair D, Roses AD, Muglia P, Francks C, Rujescu D, Meltzer HY, Goldstein DBet al., 2009, A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia, PLOS GENETICS, Vol: 5, ISSN: 1553-7404

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• Citations: 345

Gallo V, Bueno-De-Mesquita HB, Vermeulen R, Andersen PM, Kyrozis A, Linseisen J, Kaaks R, Allen NE, Roddam AW, Boshuizen HC, Peeters PH, Palli D, Mattiello A, Sieri S, Tumino R, Jimenez-Martin JM, Diaz MJ, Suarez LR, Trichopoulou A, Agudo A, Arriola L, Barricante-Gurrea A, Bingham S, Khaw KT, Manjer J, Lindkvist B, Overvad K, Bach FW, Tjonneland A, Olsen A, Bergmann MM, Boeing H, Clavel-Chapelon F, Lund E, Hallmans G, Middleton L, Vineis P, Riboli Eet al., 2009, Smoking and risk for amyotrophic lateral sclerosis: analysis of the EPIC cohort, Vol: 65, Pages: 378-385, ISSN: 1531-8249

OBJECTIVE: Cigarette smoking has been reported as "probable" risk factor for Amyotrophic Lateral Sclerosis (ALS), a poorly understood disease in terms of aetiology. The extensive longitudinal data of the European Prospective Investigation into Cancer and Nutrition (EPIC) were used to evaluate age-specific mortality rates from ALS and the role of cigarette smoking on the risk of dying from ALS. METHODS: A total of 517,890 healthy subjects were included, resulting in 4,591,325 person-years. ALS cases were ascertained through death certificates. Cox hazard models were built to investigate the role of smoking on the risk of ALS, using packs/years and smoking duration to study dose-response. RESULTS: A total of 118 subjects died from ALS, resulting in a crude mortality rate of 2.69 per 100,000/year. Current smokers at recruitment had an almost two-fold increased risk of dying from ALS compared to never smokers (HR = 1.89, 95% C.I. 1.14-3.14), while former smokers at the time of enrollment had a 50% increased risk (HR = 1.48, 95% C.I. 0.94-2.32). The number of years spent smoking increased the risk of ALS (p for trend = 0.002). Those who smoked more than 33 years had more than a two-fold increased risk of ALS compared with never smokers (HR = 2.16, 95% C.I. 1.33-3.53). Conversely, the number of years since quitting smoking was associated with a decreased risk of ALS compared with continuing smoking. INTERPRETATION: These results strongly support the hypothesis of a role of cigarette smoking in aetiology of ALS. We hypothesize that this could occur through lipid peroxidation via formaldehyde exposure.

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Ishihara-Paul L, Hulihan MM, Kachergus J, Upmanyu R, Warren L, Amouri R, Elango R, Prinjha RK, Soto A, Kefi M, Zouari M, Sassi SB, Yahmed SB, El Euch-Fayeche G, Matthews PM, Middleton LT, Gibson RA, Hentati F, Farrer MJet al., 2008, <i>PINK1</i> mutations and parkinsonism, NEUROLOGY, Vol: 71, Pages: 896-902, ISSN: 0028-3878

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• Citations: 41

Hulihan MM, Ishihara-Paul L, Kochergus J, Warren L, Amouri R, Elango R, Prinjha RK, Upmanyu R, Kefi M, Zouari M, Ben Sassi S, Ben Yahmed S, El Euch-Fayeche G, Matthews PM, Middleton LT, Gibson RA, Hentati F, Farrer MJet al., 2008, LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case-control genetic study, LANCET NEUROLOGY, Vol: 7, Pages: 591-594, ISSN: 1474-4422

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• Citations: 123

Tozzi F, Prokopenko I, Perry JD, Kennedy JL, McCarthy AD, Holsboer F, Berrettini W, Middleton LT, Chilcoat HD, Muglia Pet al., 2008, Family history of depression is associated with younger age of onset in patients with recurrent depression, PSYCHOLOGICAL MEDICINE, Vol: 38, Pages: 641-649, ISSN: 0033-2917

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• Citations: 47

Nicolaou P, Georghiou A, Votsi C, Middleton LT, Zamba-Papanicolaou E, Christodoulou Ket al., 2008, A novel c.5308_5311delGAGA mutation in Senataxin in a Cypriot family with an autosomal recessive cerebellar ataxia, BMC MEDICAL GENETICS, Vol: 9, ISSN: 1471-2350

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• Citations: 23

Isihara PL, Hulihan M, Kachergus J, Middleton L, Roses ADet al., 2007, Candidate single Nucleotide Polymorphism from a Genome- Wide Association Study of Alzheimer's Disease., Archives of Neurology (In press)

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Pillai SG, Chiano MN, White NJ, Speer M, Barnes KC, Carlsen K, Gerritsen J, Helms P, Lenney W, Silverman M, Sly P, Sundy J, Tsanakas J, von Berg A, Whyte M, Varsani S, Skelding P, Hauser M, Vance J, Pericak-Vance M, Burns DK, Middleton LT, Brewster SR, Anderson WH, Riley JHet al., 2007, A genome-wide search for linkage to asthma phenotypes in the genetics of asthma international network families: evidence for a major susceptibility locus on chromosome 2p (vol 14, pg 307, 2006), EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 15, Pages: 714-714, ISSN: 1018-4813

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Webb BT, van den Oord E, Akkari A, Wilton S, Ly T, Duv R, Barnes KC, Carlsen K, Gerritsen J, Lenney W, Silverman M, Sly P, Sundy J, Tsanakas J, von Berg A, Whyte M, Blumenthal M, Vestbo J, Middleton L, Helms PJ, Anderson WH, Pillai SGet al., 2007, Quantitative linkage genome scan for atopy in a large collection of Caucasian families, HUMAN GENETICS, Vol: 121, Pages: 83-92, ISSN: 0340-6717

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• Citations: 13

Ishihara L, Gibson RA, Warren L, Amouri R, Lyons K, Wielinski C, Hunter C, Swartz JE, Elango R, Akkari PA, Leppert D, Surh L, Reeves KH, Thomas S, Ragone L, Hattori N, Pahwa R, Jankovic J, Nance M, Freeman A, Gouider-Khouja N, Kefi M, Zouari M, Ben Sassi S, Ben Yahmed S, El Euch-Fayeche G, Middleton L, Burn DJ, Watts RL, Hentati Fet al., 2007, Screening for Lrrk2 G2019S and clinical comparison of Tunisian and North American Caucasian Parkinson's disease families, MOVEMENT DISORDERS, Vol: 22, Pages: 55-61, ISSN: 0885-3185

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• Citations: 67

Prokopenko I, Tozzi F, Vicentini E, Vanzo A, Brewster S, Perry J, Chissoe S, Jean PS, Bansal A, Upmanyu R, Budde L, Allan C, Riley J, Domenici E, Merlo-Pich E, McCarthy A, Iolsboer F, Roses A, Middleton L, Berrettini W, Kennedy J, Muglia Pet al., 2006, Major depressive disorder: Genetic association analyses using subphenotypes, 14th World Congress on Psychiatric Genetics, Publisher: WILEY, Pages: 809-809, ISSN: 1552-4841

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Domenici E, Prokopenko I, Wille D, Tozzi F, McCarthy A, Weber B, Middleton L, Muglia Pet al., 2006, Identification of diagnostic biomarkers for depression by multi analyte profiling of peripheral samples from case/control collections, 14th World Congress on Psychiatric Genetics, Publisher: WILEY-LISS, Pages: 790-790, ISSN: 1552-4841

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• Citations: 1

Muglia P, Tozzi F, Prokopenko I, McCarthy A, Brewster S, Perry J, Chissoe S, St Jean P, Bansal A, Allan C, Riley J, Domenici E, Merlo-Pich E, Holsboer F, Middleton L, Roses Aet al., 2006, A large scale depression case-control study and its impact on drug discovery & development, 14th World Congress on Psychiatric Genetics, Publisher: WILEY-LISS, Pages: 690-690, ISSN: 1552-4841

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Ishihara L, Warren L, Gibson R, Amouri R, Lesage S, Durr A, Tazir M, Wszolek ZK, Uitti RJ, Nichols WC, Griffith A, Hattori N, Leppert D, Watts R, Zabetian CP, Foroud TM, Farrer MJ, Brice A, Middleton L, Hentati Fet al., 2006, Clinical features of Parkinson disease patients with homozygous leucine-rich repeat kinase 2 G2019S mutations, ARCHIVES OF NEUROLOGY, Vol: 63, Pages: 1250-1254, ISSN: 0003-9942

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• Citations: 77

Pillai SG, Chiano MN, White NJ, Speer M, Barnes KC, Carlsen K, Gerritsen J, Helms P, Lenney W, Silverman M, Sly P, Sundy J, Tsanakas J, von Berg A, Whyte M, Varsani S, Skelding P, Hauser M, Vance J, Pericak-Vance M, Burns DK, Middleton LT, Brewster SR, Anderson WH, Riley JHet al., 2006, A genome-wide search for linkage to asthma phenotypes in the genetics of asthma international network families: evidence for a major susceptibility locus on chromosome 2p, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 14, Pages: 307-316, ISSN: 1018-4813

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• Citations: 33

Van den Oord EJCG, Rujescu D, Robles JR, Giegling I, Birrell C, Bukszár J, Murrelle L, Möller HJ, Middleton L, Muglia Pet al., 2006, Factor structure and external validity of the PANSS revisited, SCHIZOPHRENIA RESEARCH, Vol: 82, Pages: 213-223, ISSN: 0920-9964

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• Citations: 114

McGuffin P, Knight J, Breen G, Brewster S, Boyd PR, Craddock N, Gill M, Korszun A, Maier W, Middleton L, Mors O, Owen MJ, Perry J, Preisig M, Reich T, Rice J, Rietschel M, Jones L, Sham P, Farmer AEet al., 2005, Whole genome linkage scan of recurrent depressive disorder from the depression network study, HUMAN MOLECULAR GENETICS, Vol: 14, Pages: 3337-3345, ISSN: 0964-6906

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• Citations: 122

Yu Y, Wyszynski DF, Waterworth DM, Wilton SD, Barter PJ, Kesäniemi YA, Mahley RW, McPherson R, Waeber G, Bersot TP, Ma Q, Sharma SS, Montgomery DS, Middleton LT, Sundseth SS, Mooser V, Grundy SM, Farrer LAet al., 2005, Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia., J Lipid Res, Vol: 46, Pages: 2202-2213, ISSN: 0022-2275

We conducted a genome-wide scan using variance components linkage analysis to localize quantitative-trait loci (QTLs) influencing triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol, and total cholesterol (TC) levels in 3,071 subjects from 459 families with atherogenic dyslipidemia. The most significant evidence for linkage to TG levels was found in a subset of Turkish families at 11q22 [logarithm of the odds ratio (LOD)=3.34] and at 17q12 (LOD=3.44). We performed sequential oligogenic linkage analysis to examine whether multiple QTLs jointly influence TG levels in the Turkish families. These analyses revealed loci at 20q13 that showed strong epistatic effects with 11q22 (conditional LOD=3.15) and at 7q36 that showed strong epistatic effects with 17q12 (conditional LOD=3.21). We also found linkage on the 8p21 region for TG in the entire group of families (LOD=3.08). For HDL-C levels, evidence of linkage was identified on chromosome 15 in the Turkish families (LOD=3.05) and on chromosome 5 in the entire group of families (LOD=2.83). Linkage to QTLs for TC was found at 8p23 in the entire group of families (LOD=4.05) and at 5q13 in a subset of Turkish and Mediterranean families (LOD=3.72). These QTLs provide important clues for the further investigation of genes responsible for these complex lipid phenotypes. These data also indicate that a large proportion of the variance of TG levels in the Turkish population is explained by the interaction of multiple genetic loci.

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Yu Y, Wyszynski DF, Waterworth DM, Wilton SD, Barter PJ, Kesäniemi YA, Mahley RW, McPherson R, Waeber G, Bersot TP, Ma QL, Sharma SS, Montgomery DS, Middleton LT, Sundseth SS, Mooser V, Grundy SM, Farrer LAet al., 2005, Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia, JOURNAL OF LIPID RESEARCH, Vol: 46, Pages: 2202-2213, ISSN: 0022-2275

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• Citations: 39

Prokopenko I, Tozzi F, Perry JD, McCarthy AD, Chissoe SL, St Jean PL, Alalouff S, Brewster SR, Kennedy JL, Middleton LT, Holsboer F, Muglia Pet al., 2005, Major depressive disorder: Identifying phenotypic subtypes for genetic studies., 13th World Congress on Psychiatric Genetics, Publisher: WILEY, Pages: 107-107, ISSN: 1552-4841

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McCarthy AD, Kennedy JL, Middleton LT, 2005, Pharmacogenetics in drug development, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 360, Pages: 1579-1588, ISSN: 0962-8436

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• Citations: 15

Roses AD, Burns DK, Chissoe S, Middleton L, Jean PSet al., 2005, Disease-specific target selection: a critical first step down the right road, DRUG DISCOVERY TODAY, Vol: 10, Pages: 177-189, ISSN: 1359-6446

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• Citations: 40

Wyszynski DF, Waterworth DM, Barter PJ, Cohen J, Kesäniemi YA, Mahley RW, McPherson R, Waeber G, Bersot TP, Sharma SS, Nolan V, Middleton LT, Sundseth SS, Farrer LA, Mooser V, Grundy SMet al., 2005, Relation between atherogenic dyslipidemia and the adult treatment programm-ill definition of metabolic syndrome (genetic epidemiology of metabolic syndrome project), AMERICAN JOURNAL OF CARDIOLOGY, Vol: 95, Pages: 194-198, ISSN: 0002-9149

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• Citations: 54

Hauser ER, Crossman DC, Granger CB, Haines JL, Jones CJH, Mooser V, McAdam B, Winkelmann BR, Wiseman AH, Muhlestein JB, Bartel AG, Dennis CA, Dowdy E, Estabrooks S, Eggleston K, Francis S, Roche K, Clevenger PW, Huang L, Pedersen B, Shah S, Schmidt S, Haynes C, West S, Asper D, Booze M, Sharma S, Sundseth S, Middleton L, Roses AD, Hauser MA, Vance JM, Pericak-Vance MA, Kraus WEet al., 2004, A genomewide scan for early-onset coronary artery disease in 438 families: The GENECARD Study, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 75, Pages: 436-447, ISSN: 0002-9297

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• Citations: 135

Li YJ, Oliveira SA, Xu PT, Martin ER, Stenger JE, Scherzer CR, Hauser MA, Scott WK, Small GW, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Jankovic J, Goetz CG, Mastaglia F, Middleton LT, Roses AD, Saunders AM, Schmechel DE, Gullans SR, Haines JL, Gilbert JR, Vance JM, Pericak-Vance MAet al., 2003, Glutathione <i>S</i>-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease, HUMAN MOLECULAR GENETICS, Vol: 12, Pages: 3259-3267, ISSN: 0964-6906

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• Citations: 189

Pillai SG, St Jean PL, Yarnall DP, Wagner MJ, Sundseth SS, DeMent RM, Riley JH, Seghal SX, Fleming TK, Hill SN, Bennett GC, Brewster SR, Meldrum EC, Purvis IJ, Middleton LT, Burns DK, Spurr NK, Roses AD, Hosford DA, Chissoe SLet al., 2003, A high throughput genetic association study of tractable genes in asthma., Annual Meeting of the American-Society-of-Human-Genetics, Publisher: UNIV CHICAGO PRESS, Pages: 525-525, ISSN: 0002-9297

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Oliveira SA, Martin ER, Scott WK, Zhang F, Stajich JM, Middleton LT, Roses AD, Scott BL, Fujiwara K, Pericak-Vance MA, Vance JMet al., 2003, Defining the linkage disequilibrium region containing the Tau gene and identifying haplotype tagging polymorphisms, Annual Meeting of the American-Society-of-Human-Genetics, Publisher: UNIV CHICAGO PRESS, Pages: 532-532, ISSN: 0002-9297

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Middleton L, 2003, Genetics of complex disorders and drug discovery, British Human Genetics Conference, Publisher: B M J PUBLISHING GROUP, Pages: S13-S13, ISSN: 1468-6244

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Schmith VD, Campbell DA, Sehgal S, Anderson WH, Burns DK, Middleton LT, Roses ADet al., 2003, Pharmacogenetics and disease genetics of complex diseases, CELLULAR AND MOLECULAR LIFE SCIENCES, Vol: 60, Pages: 1636-1646, ISSN: 1420-682X

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• Citations: 25