A generalizable hypothesis for the genetic architecture of disease: pleomorphic risk loci

被引：65

作者：

Singleton, Andrew ^{[3
]}

Hardy, John ^{[1
,2
]}

机构：

[1] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England

[2] Inst Neurol, Reta Lilla Weston Labs, London WC1N 3BG, England

[3] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

来源：

HUMAN MOLECULAR GENETICS | 2011年 / 20卷

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; FACTOR-H POLYMORPHISM; APOLIPOPROTEIN-E; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; RARE VARIANTS; MUTATIONS; SUSCEPTIBILITY; DUPLICATION; EXPRESSION;

D O I：

10.1093/hmg/ddr358

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The dominant and sometimes competing theories for the aetiology of complex human disease have been the common disease, common variant (CDCV) hypothesis, and the multiple rare variant (MRV) hypothesis. With the advent of genome wide association studies and of second-generation sequencing, we are fortunate in being able to test these ideas. The results to date suggest that these hypotheses are not mutually exclusive. Further, initial evidence suggests that both MRV and CDCV can be true at the same loci, and that other disease-related genetic mechanisms also exist at some of these loci. We propose calling these, pleomorphic risk loci, and discuss here how such loci not only offer understanding of the genetic basis of disease, but also provide mechanistic biological insight into disease processes.

引用

页码：R158 / R162

页数：5

共 34 条

[1]

Hundreds of variants clustered in genomic loci and biological pathways affect human height [J].

Allen, Hana Lango ;

Estrada, Karol ;

Lettre, Guillaume ;

Berndt, Sonja I. ;

Weedon, Michael N. ;

Rivadeneira, Fernando ;

Willer, Cristen J. ;

Jackson, Anne U. ;

Vedantam, Sailaja ;

Raychaudhuri, Soumya ;

Ferreira, Teresa ;

Wood, Andrew R. ;

Weyant, Robert J. ;

Segre, Ayellet V. ;

Speliotes, Elizabeth K. ;

Wheeler, Eleanor ;

Soranzo, Nicole ;

Park, Ju-Hyun ;

Yang, Jian ;

Gudbjartsson, Daniel ;

Heard-Costa, Nancy L. ;

Randall, Joshua C. ;

Qi, Lu ;

Smith, Albert Vernon ;

Maegi, Reedik ;

Pastinen, Tomi ;

Liang, Liming ;

Heid, Iris M. ;

Luan, Jian'an ;

Thorleifsson, Gudmar ;

Winkler, Thomas W. ;

Goddard, Michael E. ;

Lo, Ken Sin ;

Palmer, Cameron ;

Workalemahu, Tsegaselassie ;

Aulchenko, Yurii S. ;

Johansson, Asa ;

Zillikens, M. Carola ;

Feitosa, Mary F. ;

Esko, Tonu ;

Johnson, Toby ;

Ketkar, Shamika ;

Kraft, Peter ;

Mangino, Massimo ;

Prokopenko, Inga ;

Absher, Devin ;

Albrecht, Eva ;

Ernst, Florian ;

Glazer, Nicole L. ;

Hayward, Caroline .

NATURE, 2010, 467 (7317) :832-838

[2]

α-synuclein locus duplication as a cause of familial Parkinson's disease [J].

Chartier-Harlin, MC ;

Kachergus, J ;

Roumier, C ;

Mouroux, V ;

Douay, X ;

Lincoln, S ;

Levecque, C ;

Larvor, L ;

Andrieux, J ;

Hulihan, M ;

Waucquier, N ;

Defebvre, L ;

Amouyel, P ;

Farrer, M ;

Destée, A .

LANCET, 2004, 364 (9440) :1167-1169

[3]

APOLIPOPROTEIN-E, EPSILON-4 ALLELE AS A MAJOR RISK FACTOR FOR SPORADIC EARLY AND LATE-ONSET FORMS OF ALZHEIMERS-DISEASE - ANALYSIS OF THE 19Q13.2 CHROMOSOMAL REGION [J].

CHARTIERHARLIN, MC ;

PARFITT, M ;

LEGRAIN, S ;

PEREZTUR, J ;

BROUSSEAU, T ;

EVANS, A ;

BERR, C ;

VIDAL, O ;

ROQUES, P ;

GOURLET, V ;

FRUCHART, JC ;

DELACOURTE, A ;

ROSSOR, M ;

AMOUYEL, P .

HUMAN MOLECULAR GENETICS, 1994, 3 (04) :569-574

[4]

GENE DOSE OF APOLIPOPROTEIN-E TYPE-4 ALLELE AND THE RISK OF ALZHEIMERS-DISEASE IN LATE-ONSET FAMILIES [J].

CORDER, EH ;

SAUNDERS, AM ;

STRITTMATTER, WJ ;

SCHMECHEL, DE ;

GASKELL, PC ;

SMALL, GW ;

ROSES, AD ;

HAINES, JL ;

PERICAKVANCE, MA .

SCIENCE, 1993, 261 (5123) :921-923

[5]

Complement factor H polymorphism and age-related macular degeneration [J].

Edwards, AO ;

Ritter, R ;

Abel, KJ ;

Manning, A ;

Panhuysen, C ;

Farrer, LA .

SCIENCE, 2005, 308 (5720) :421-424

[6]

FATAL FAMILIAL INSOMNIA AND FAMILIAL CREUTZFELDT-JAKOB DISEASE - DISEASE PHENOTYPE DETERMINED BY A DNA POLYMORPHISM [J].

GOLDFARB, LG ;

PETERSEN, RB ;

TABATON, M ;

BROWN, P ;

LEBLANC, AC ;

MONTAGNA, P ;

CORTELLI, P ;

JULIEN, J ;

VITAL, C ;

PENDELBURY, WW ;

HALTIA, M ;

WILLS, PR ;

HAUW, JJ ;

MCKEEVER, PE ;

MONARI, L ;

SCHRANK, B ;

SWERGOLD, GD ;

AUTILIOGAMBETTI, L ;

GAJDUSEK, DC ;

LUGARESI, E ;

GAMBETTI, P .

SCIENCE, 1992, 258 (5083) :806-808

[7]

Complement factor H variant increases the risk of age-related macular degeneration [J].

Haines, JL ;

Hauser, MA ;

Schmidt, S ;

Scott, WK ;

Olson, LM ;

Gallins, P ;

Spencer, KL ;

Kwan, SY ;

Noureddine, M ;

Gilbert, JR ;

Schnetz-Boutaud, N ;

Agarwal, A ;

Postel, EA ;

Pericak-Vance, MA .

SCIENCE, 2005, 308 (5720) :419-421

[8]

CURRENT CONCEPTS Genomewide Association Studies and Human Disease [J].

Hardy, John ;

Singleton, Andrew .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 360 (17) :1759-1768

[9]

Potential etiologic and functional implications of genome-wide association loci for human diseases and traits [J].

Hindorff, Lucia A. ;

Sethupathy, Praveen ;

Junkins, Heather A. ;

Ramos, Erin M. ;

Mehta, Jayashri P. ;

Collins, Francis S. ;

Manolio, Teri A. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (23) :9362-9367

[10]

Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 [J].

Hutton, M ;

Lendon, CL ;

Rizzu, P ;

Baker, M ;

Froelich, S ;

Houlden, H ;

Pickering-Brown, S ;

Chakraverty, S ;

Isaacs, A ;

Grover, A ;

Hackett, J ;

Adamson, J ;

Lincoln, S ;

Dickson, D ;

Davies, P ;

Petersen, RC ;

Stevens, M ;

de Graaff, E ;

Wauters, E ;

van Baren, J ;

Hillebrand, M ;

Joosse, M ;

Kwon, JM ;

Nowotny, P ;

Che, LK ;

Norton, J ;

Morris, JC ;

Reed, LA ;

Trojanowski, J ;

Basun, H ;

Lannfelt, L ;

Neystat, M ;

Fahn, S ;

Dark, F ;

Tannenberg, T ;

Dodd, PR ;

Hayward, N ;

Kwok, JBJ ;

Schofield, PR ;

Andreadis, A ;

Snowden, J ;

Craufurd, D ;

Neary, D ;

Owen, F ;

Oostra, BA ;

Hardy, J ;

Goate, A ;

van Swieten, J ;

Mann, D ;

Lynch, T .

NATURE, 1998, 393 (6686) :702-705

← 1 2 3 4 →