Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration

Human Molecular Genetics

Volumn 23, Issue 21, 2014, Pages 5827-5837

  Ratnapriya, Rinki ^a   Zhan, Xiaowei ^b,c   Fariss, Robert N ^a   Branham, Kari E ^d   Zipprer, David ^a   Chakarova, Christina F ^e   Sergeev, Yuri V ^a   Campos, Maria M ^a   Othman, Mohammad ^d   Friedman, James S ^a   Maminishkis, Arvydas ^a   Waseem, Naushin H ^e   Brooks, Matthew ^a   Rajasimha, Harsha K ^a   Edwards, Albert O ^f   Lotery, Andrew ^g   Klein, Barbara E ^h   Truitt, Barbara J ⁱ   Li, Bingshan ^j   Schaumberg, Debra A ^k,l   Morgan, Denise J ^l   Morrison, Margaux A ^l   Souied, Eric ^m   Tsironi, Evangelia E ⁿ   Grassmann, Felix ^o   Fishman, Gerald A ^p   Silvestri, Giuliana ^q   Scholl, Hendrik P N ^r   Kim, Ivana K ^s   Ramke, Jacqueline ^t,u   Tuo, Jingsheng ^a   Merriam, Joanna E ^v   Merriam, John C ^v   Park, Kyu Hyung ^x   Olson, Lana M ^j   Farrer, Lindsay A ^y,al   Johnson, Matthew P ^z   Peachey, Neal S ^aa,ab   Lathrop, Mark ^ac   Baron, Robert V ^ad   Igo, Robert P ⁱ   Klein, Ronald ^h   Hagstrom, Stephanie A ^aa   Kamatani, Yoichiro ^ac   Martin, Tammy M ^ae   Jiang, Yingda ^ad   Conley, Yvette ^af   Sahel, Jose Alan ^ac   Zack, Donald J ^r   Chan, Chi Chao ^a   Pericak Vance, Margaret A ^ag   Jacobson, Samuel G ^ah   Gorin, Michael B ^ai   Klein, Michael L ^aj   Allikmets, Rando ^v,w   Iyengar, Sudha K ⁱ   Weber, Bernhard H ^o   Haines, Jonathan L ^j   Léveillard, Thierry ^ac   Deangelis, Margaret M ^l   Stambolian, Dwight ^ak   Weeks, Daniel E ^ad   Bhattacharya, Shomi S ^e   Chew, Emily Y ^a   Heckenlively, John R ^d   Abecasis, Gonçalo R ^b,c   Swaroop, Anand ^a   more..

^a NATIONAL EYE INSTITUTE   (United States)

^b UNIVERSITY OF MICHIGAN   (United States)

^c UNIVERSITY OF MICHIGAN SCHOOL OF PUBLIC HEALTH   (United States)

^d UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^e UCLInstitute of Ophthalmology   (United Kingdom)

^f UNIVERSITY OF OREGON   (United States)

^g UNIVERSITY OF SOUTHAMPTON   (United Kingdom)

^h UNIVERSITY OF WISCONSIN SCHOOL OF MEDICINE AND PUBLIC HEALTH   (United States)

ⁱ CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^j VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^k BRIGHAM AND WOMEN S HOSPITAL   (United States)

^l UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

^m UNIVERSITÉ PARIS EST CRÉTEIL   (France)

ⁿ UNIVERSITY OF THESSALY   (Greece)

^o UNIVERSITY OF REGENSBURG   (Germany)

^p UNIVERSITY OF ILLINOIS AT CHICAGO   (United States)

^q QUEEN'S UNIVERSITY BELFAST   (United Kingdom)

^r JOHNS HOPKINS UNIVERSITY   (United States)

^s HARVARD MEDICAL SCHOOL   (United States)

^t Fred Hollows Foundation New Zealand   (New Zealand)

^u UNIVERSITY OF NEW SOUTH WALES   (Australia)

^v Och Spine at New York Presbyterian Hospitals   (United States)

^w NewYork Presbyterian Hospital   (United States)

^x Seoul National University Bundang Hospital   (South Korea)

^y BOSTON UNIVERSITY   (United States)

^z SOUTHWEST FOUNDATION FOR BIOMEDICAL RESEARCH   (United States)

^aa LERNER RESEARCH INSTITUTE   (United States)

^ab LOUIS STOKES CLEVELAND VA MEDICAL CENTER   (United States)

^ac INSERM   (France)

^ad UNIVERSITY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH   (United States)

^ae OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^af University School of Nursing   (United States)

^ag UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

^ah UNIVERSITY OF PENNSYLVANIA   (United States)

^ai UNIVERSITY OF CALIFORNIA   (United States)

^aj UNIVERSITY OF PORTLAND   (United States)

^ak UNIVERSITY OF PENNSYLVANIA   (United States)

^al BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ELASTIN; FIBRILLIN 2; ACTIN BINDING PROTEIN; FIBRILLIN;

AGE RELATED MACULAR DEGENERATION; AGED; AGING; ANIMAL TISSUE; ARTICLE; AUTOSOMAL DOMINANT INHERITANCE; BRUCH MEMBRANE; CLINICAL ARTICLE; CONTROLLED STUDY; EXOME; EXTRACELLULAR MATRIX; GENE; GENE EXPRESSION; GENE SEQUENCE; GENETIC VARIABILITY; GENOTYPE; HUMAN; HUMAN TISSUE; MACULAR DEGENERATION; MALE; MOLECULAR MODEL; NONHUMAN; NUCLEOTIDE SEQUENCE; PEDIGREE; PHENOTYPE; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN STABILITY; RETINA; RETINA MACULOPATHY; ADULT; AMINO ACID SEQUENCE; CHEMICAL STRUCTURE; GENETIC ASSOCIATION; GENETICS; HIGH THROUGHPUT SEQUENCING; META ANALYSIS (TOPIC); METABOLISM; MIDDLE AGED; MOLECULAR GENETICS; MUTATION; PATHOLOGY; PROTEIN CONFORMATION; SEQUENCE ALIGNMENT;

ADULT; AGED; AMINO ACID SEQUENCE; BRUCH MEMBRANE; DNA MUTATIONAL ANALYSIS; EXOME; EXTRACELLULAR MATRIX; GENETIC ASSOCIATION STUDIES; GENETIC VARIATION; HIGH-THROUGHPUT NUCLEOTIDE SEQUENCING; HUMANS; MACULAR DEGENERATION; MALE; META-ANALYSIS AS TOPIC; MICROFILAMENT PROTEINS; MIDDLE AGED; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; MUTATION; PEDIGREE; PROTEIN CONFORMATION; PROTEIN STABILITY; RETINA; SEQUENCE ALIGNMENT;

EID: 84911391197     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddu276     Document Type: Article

References (64)

1. Stone, E.M. (2007) Macular degeneration. Annu. Rev. Med., 58, 477-490.
2. Rattner, A. and Nathans, J. (2006) Macular degeneration: recent advances and therapeutic opportunities. Nat. Rev. Neurosci., 7, 860-872.
3. Jager, R.D., Mieler, W.F. and Miller, J.W. (2008) Age-related macular degeneration. N. Engl. J. Med., 358, 2606-2617.
4. Swaroop, A., Chew, E.Y., Rickman, C.B. and Abecasis, G.R. (2009) Unraveling a multifactorial late-onset disease: from genetic susceptibility to disease mechanisms for age-related macular degeneration. Annu. Rev. Genomics Hum. Genet., 10, 19-43.
5. Hageman, G.S., Luthert, P.J., Victor Chong, N.H., Johnson, L.V., Anderson, D.H. and Mullins, R.F. (2001) An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog. Retin. Eye Res., 20, 705-732.
6. Huang, J.D., Presley, J.B., Chimento, M.F., Curcio, C.A. and Johnson, M. (2007) Age-related changes in humanmacular Bruch'smembrane as seen by quick-freeze/deep-etch. Exp. Eye. Res., 85, 202-218.
7. Neale, B.M., Fagerness, J., Reynolds, R., Sobrin, L., Parker, M., Raychaudhuri, S., Tan, P.L., Oh, E.C., Merriam, J.E., Souied, E. et al. (2010) Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc. Natl. Acad. Sci. USA, 107, 7395-7400.
8. Chen, W., Stambolian, D., Edwards, A.O., Branham, K.E., Othman, M., Jakobsdottir, J., Tosakulwong, N., Pericak-Vance, M.A., Campochiaro, P.A., Klein, M.L. et al. (2010) Genetic variants nearTIMP3and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc. Natl. Acad. Sci. USA, 107, 7401-7406.
9. Fritsche, L.G., Chen, W., Schu, M., Yaspan, B.L., Yu, Y., Thorleifsson, G., Zack, D.J., Arakawa, S., Cipriani, V., Ripke, S. et al. (2013) Seven new loci associated with age-related macular degeneration. Nat. Genet., 45, 433-439.
10. Priya, R.R., Chew, E.Y. and Swaroop, A. (2012) Genetic studies of age-related macular degeneration: lessons, challenges, and opportunities for disease management. Ophthalmology, 119, 2526-2536.
11. Gorin, M.B. (2012) Genetic insights into age-related macular degeneration: controversies addressing risk, causality, and therapeutics. Mol. Aspects Med., 33, 467-486.
12. Zheng, W., Reem, R.E., Omarova, S., Huang, S., DiPatre, P.L., Charvet, C.D., Curcio, C.A. and Pikuleva, I.A. (2012) Spatial distribution of the pathways of cholesterol homeostasis in human retina. PLoS One, 7, e37926.
13. Allikmets, R., Singh, N., Sun, H., Shroyer, N.F., Hutchinson, A., Chidambaram, A., Gerrard, B., Baird, L., Stauffer, D., Peiffer, A. et al. (1997)Aphotoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat. Genet., 15, 236-246.
14. Weber, B.H., Vogt, G., Pruett, R.C., Stohr, H. and Felbor, U. (1994) Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nat. Genet., 8, 352-356.
15. Allikmets, R. (2000) Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium. Am. J. Hum. Genet., 67, 487-491.
16. Curcio, C.A., Johnson, M., Huang, J.D. and Rudolf, M. (2009) Aging, age-related macular degeneration, and the response-to-retention of apolipoprotein B-containing lipoproteins. Prog. Retin. Eye Res., 28, 393-422.
17. Curcio, C.A., Johnson, M., Rudolf,M.and Huang, J.D. (2011) The oil spill in ageing Bruch membrane. Br. J. Ophthalmol., 95, 1638-1645.
18. Stone, E.M., Lotery, A.J., Munier, F.L., Heon, E., Piguet, B., Guymer, R.H., Vandenburgh, K., Cousin, P., Nishimura, D., Swiderski, R.E. et al. (1999)A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat. Genet., 22, 199-202.
19. Ayyagari, R., Mandal, M.N., Karoukis, A.J., Chen, L., McLaren, N.C., Lichter, M., Wong, D.T., Hitchcock, P.F., Caruso, R.C., Moroi, S.E. et al. (2005) Late-onset macular degeneration and long anterior lens zonules result from a CTRP5gene mutation. Invest. Ophthalmol. Vis. Sci., 46, 3363-3371.
20. Hayward, C., Shu, X., Cideciyan, A.V., Lennon, A., Barran, P., Zareparsi, S., Sawyer, L., Hendry, G., Dhillon, B., Milam, A.H. et al. (2003) Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration. Hum. Mol. Genet., 12, 2657-2667.
21. Fariss, R.N., Apte, S.S., Luthert, P.J., Bird, A.C. and Milam, A.H. (1998) Accumulation of tissue inhibitor of metalloproteinases-3 in humaneyes with Sorsby's fundus dystrophy or retinitis pigmentosa. Br. J. Ophthalmol., 82, 1329-1334.
22. Marmorstein, L.Y., Munier, F.L., Arsenijevic, Y., Schorderet, D.F., McLaughlin, P.J., Chung, D., Traboulsi, E. and Marmorstein, A.D. (2002) Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration. Proc. Natl. Acad. Sci. USA, 99, 13067-13072.
23. Chavali, V.R., Khan, N.W., Cukras, C.A., Bartsch, D.U., Jablonski, M.M. and Ayyagari, R. (2011) A CTRP5 gene S163R mutation knock-in mouse model for late-onset retinal degeneration. Hum. Mol. Genet., 20, 2000-2014.
24. Qi, J.H., Ebrahem, Q., Moore, N., Murphy, G., Claesson-Welsh, L., Bond, M., Baker, A. and Anand-Apte, B. (2003) A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat. Med., 9, 407-415.
25. Bird, A.C. (1992) Bruch's membrane change with age. Br. J. Ophthalmol., 76, 166-168.
26. Johnson, M., Dabholkar, A., Huang, J.D., Presley, J.B., Chimento, M.F. and Curcio, C.A. (2007) Comparison of morphology of human macular and peripheral Bruch's membrane in older eyes. Curr. Eye Res., 32, 791-799.
27. Chong, N.H., Keonin, J., Luthert, P.J., Frennesson, C.I., Weingeist, D.M., Wolf, R.L., Mullins, R.F. and Hageman, G.S. (2005) Decreased thickness and integrity of the macular elastic layer of Bruch's membrane correspond to the distribution of lesions associated with age-related macular degeneration. Am. J. Pathol., 166, 241-251.
28. Davis, M.D., Gangnon, R.E., Lee, L.Y., Hubbard, L.D., Klein, B.E., Klein, R., Ferris, F.L., Bressler, S.B. and Milton, R.C. and Age-Related Eye Disease Study, Group. (2005) The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17. Arch. Ophthalmol., 123, 1484-1498.
29. Sarks, S.H., Arnold, J.J., Killingsworth, M.C. and Sarks, J.P. (1999) Early drusen formation in the normal and aging eye and their relation to age related maculopathy: a clinicopathological study. Br. J. Ophthalmol., 83, 358-368.
30. Yu, Y., Reynolds, R., Rosner, B., Daly, M.J. and Seddon, J.M. (2012) Prospective assessment of genetic effects on progression to different stages of age-related macular degeneration using multistate Markov models. Invest. Ophthalmol. Vis. Sci., 53, 1548-1556.
31. Olivieri, J., Smaldone, S. and Ramirez, F. (2010) Fibrillin assemblies: extracellular determinants of tissue formation and fibrosis. Fibrogenesis Tissue Repair, 3, 24.
32. Ramirez, F. and Dietz, H.C. (2007) Fibrillin-rich microfibrils: structural determinants of morphogenetic and homeostatic events. J. Cell. Physiol., 213, 326-330.
33. Putnam, E.A., Zhang, H., Ramirez, F. and Milewicz, D.M. (1995) Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. Nat. Genet., 11, 456-458.
34. Dietz, H.C., Cutting, G.R., Pyeritz, R.E., Maslen, C.L., Sakai, L.Y., Corson, G.M., Puffenberger, E.G., Hamosh, A., Nanthakumar, E.J., Curristin, S.M. et al. (1991) Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature, 352, 337-339.
35. Johnson, L.V. and Anderson, D.H. (2004) Age-related macular degeneration and the extracellular matrix. N. Engl. J. Med., 351, 320-322.
36. Klenotic, P.A., Munier, F.L., Marmorstein, L.Y. and Anand-Apte, B. (2004) Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a binding partner of epithelial growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1). Implications for macular degenerations. J. Biol. Chem., 279, 30469-30473.
37. Park, E.S., Putnam, E.A., Chitayat, D., Child, A. and Milewicz, D.M. (1998) Clustering of FBN2 mutations in patients with congenital contractural arachnodactyly indicates an important role of the domains encoded by exons 24 through 34 during human development. Am. J. Hum. Genet., 78, 350-355.
38. Callewaert, B.L., Loeys, B.L., Ficcadenti, A., Vermeer, S., Landgren, M., Kroes, H.Y., Yaron, Y., Pope, M., Foulds, N., Boute, O. et al. (2009) Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: report of 14 novel mutations and review of the literature. Hum. Mut., 30, 334-341.
39. Ramirez, F. and Sakai, L.Y. (2010) Biogenesis and function of fibrillin assemblies. Cell Tissue Res., 339, 71-82.
40. Pruim, R.J., Welch, R.P., Sanna, S., Teslovich, T.M., Chines, P.S., Gliedt, T.P., Boehnke, M., Abecasis, G.R. and Willer, C.J. (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics, 26, 2336-2337.
41. Wells, J.,Wroblewski, J., Keen, J., Inglehearn, C., Jubb, C., Eckstein, A., Jay, M., Arden, G., Bhattacharya, S., Fitzke, F. et al. (1993) Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy. Nat. Genet., 3, 213-218.
42. Nemet, A.Y., Assia, E.I., Apple, D.J. and Barequet, I.S. (2006) Current concepts of ocular manifestations in Marfan syndrome. Surv. Ophthalmol., 51, 561-575.
43. Takaesu-Miyagi, S., Sakai, H., Shiroma, T., Hayakawa, K., Funakoshi, Y. and Sawaguchi, S. (2004) Ocular findings of Beals syndrome. Jpn. J. Ophthalmol., 48, 470-474.
44. Gallego-Pinazo, R., Lopez-Lizcano, R., Millan, J.M., Arevalo, J.F., Mullor, J.L. and Diaz-Llopis, M. (2010) Beals-Hecht syndrome and choroidal neovascularization. Clin. Ophthalmol., 4, 845-847.
45. Mariencheck, M.C., Davis, E.C., Zhang, H., Ramirez, F., Rosenbloom, J., Gibson, M.A., Parks, W.C. and Mecham, R.P. (1995) Fibrillin-1 and fibrillin-2 show temporal and tissue-specific regulation of expression in developing elastic tissues. Connect. Tissue Res., 31, 87-97.
46. Nagineni, C.N., Samuel, W., Nagineni, S., Pardhasaradhi, K., Wiggert, B., Detrick, B. and Hooks, J.J. (2003) Transforming growth factor-beta induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: involvement of mitogen-activated protein kinases. J. Cell. Physiol., 197, 453-462.
47. Chakravarti, A., Clark, A.G. and Mootha, V.K. (2013) Distilling pathophysiology from complex disease genetics. Cell, 155, 21-26.
48. Cirulli, E.T. and Goldstein, D.B. (2010) Uncovering the roles of rare variants incommondisease through whole-genome sequencing. Nat. Rev. Genet., 11, 415-425.
49. Gibson, G. (2011) Rare and common variants: twenty arguments. Nat. Rev. Genet., 13, 135-145.
50. Zuk, O., Hechter, E., Sunyaev, S.R. and Lander, E.S. (2012) The mystery of missing heritability: genetic interactions create phantom heritability. Proc. Natl. Acad. Sci. USA, 109, 1193-1198.
51. Raychaudhuri, S., Iartchouk, O., Chin, K., Tan, P.L., Tai, A.K., Ripke, S., Gowrisankar, S., Vemuri, S., Montgomery, K., Yu, Y. et al. (2011) A rare penetrant mutation in CFH confers high risk of age-related macular degeneration. Nat. Genet., 43, 1232-1236.
52. Seddon, J.M., Yu, Y., Miller, E.C., Reynolds, R., Tan, P.L., Gowrisankar, S., Goldstein, J.I., Triebwasser, M., Anderson, H.E., Zerbib, J. et al. (2013) Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat. Genet., 45, 1366-1370.
53. van de Ven, J.P., Nilsson, S.C., Tan, P.L., Buitendijk, G.H., Ristau, T., Mohlin, F.C., Nabuurs, S.B., Schoenmaker-Koller, F.E., Smailhodzic, D., Campochiaro, P.A. et al. (2013)Afunctional variant in the CFI gene confers a high risk of age-related macular degeneration. Nat. Genet., 45, 813-817.
54. Helgason, H., Sulem, P., Duvvari, M.R., Luo, H., Thorleifsson, G., Stefansson, H., Jonsdottir, I., Masson, G., Gudbjartsson, D.F., Walters, G.B. et al. (2013) A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nat. Genet., 45, 1371-1374.
55. Zhan, X., Larson, D.E., Wang, C., Koboldt, D.C., Sergeev, Y.V., Fulton, R.S., Fulton, L.L., Fronick, C.C., Branham, K.E., Bragg-Gresham, J. et al. (2013) Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nat. Genet., 45, 1375-1379.
56. Li, H. and Durbin, R. (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics, 25, 1754-1760.
57. Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G. and Durbin, R. (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics, 25, 2078-2079.
58. Wang, K., Li, M. and Hakonarson, H. (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res., 38, e164.
59. Ponting, C.P., Schultz, J., Milpetz, F. and Bork, P. (1999) SMART: identification and annotation of domains from signalling and extracellular protein sequences. Nucleic Acids Res., 27, 229-232.
60. Kiefer, F., Arnold, K., Kunzli, M., Bordoli, L. and Schwede, T. (2009) The SWISS-MODEL Repository and associated resources. Nucleic Acids Res., 37, D387-e37392.
61. Krieger, E., Nabuurs, S.B. and Vriend, G. (2003) Homology modeling. Methods Biochem. Anal., 44, 509-523.
62. Chen,W.M., Manichaikul,A. andRich, S.S. (2009)Ageneralizedfamily-based association test for dichotomous traits. Am. J. Hum.Genet., 85, 364-376.
63. Willer, C.J., Li, Y. and Abecasis, G.R. (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics, 26, 2190-2191.
64. Higgins, J.P., Thompson, S.G., Deeks, J.J. and Altman, D.G. (2003) Measuring inconsistency in meta-analyses. BMJ., 327, 557-560.