Genome-wide association for major depressive disorder: A possible role for the presynaptic protein piccolo

P. F. Sullivan; E. J.C. De Geus; G. Willemsen; M. R. James; J. H. Smit; T. Zandbelt; V. Arolt; B. T. Baune; D. Blackwood; S. Cichon; W. L. Coventry; K. Domschke; A. Farmer; M. Fava; S. D. Gordon; Q. He; A. C. Heath; P. Heutink; F. Holsboer; W. J. Hoogendijk; J. J. Hottenga; Y. Hu; M. Kohli; D. Lin; S. Lucae; D. J. MacIntyre; W. Maier; K. A. McGhee; P. McGuffin; G. W. Montgomery; W. J. Muir; W. A. Nolen; M. M. Nöthen; R. H. Perlis; K. Pirlo; D. Posthuma; M. Rietschel; P. Rizzu; A. Schosser; A. B. Smit; J. W. Smoller; J. Y. Tzeng; R. Van Dyck; M. Verhage; F. G. Zitman; N. G. Martin; N. R. Wray; D. I. Boomsma; B. W.J.H. Penninx

doi:10.1038/mp.2008.125

Genome-wide association for major depressive disorder: A possible role for the presynaptic protein piccolo

P. F. Sullivan
, E. J.C. De Geus
, G. Willemsen
, M. R. James
, J. H. Smit
, T. Zandbelt
, V. Arolt
, B. T. Baune
, D. Blackwood
, S. Cichon
, W. L. Coventry
, K. Domschke
, A. Farmer
, M. Fava
, S. D. Gordon
, Q. He
, A. C. Heath
, P. Heutink
, F. Holsboer
, W. J. Hoogendijk

J. J. Hottenga, Y. Hu, M. Kohli, D. Lin, S. Lucae, D. J. MacIntyre, W. Maier, K. A. McGhee, P. McGuffin, G. W. Montgomery, W. J. Muir, W. A. Nolen, M. M. Nöthen, R. H. Perlis, K. Pirlo, D. Posthuma, M. Rietschel, P. Rizzu, A. Schosser, A. B. Smit, J. W. Smoller, J. Y. Tzeng, R. Van Dyck, M. Verhage, F. G. Zitman, N. G. Martin, N. R. Wray, D. I. Boomsma, B. W.J.H. Penninx

University of North Carolina at Chapel Hill
Vrije Universiteit Amsterdam
Queensland Institute of Medical Research
VU University Medical Center
University of Münster
James Cook University Queensland
University of Edinburgh
University of Bonn
University of New England
King's College London
Harvard University
Washington University St. Louis
Max Planck Institute of Psychiatry
NHS Lothian
University of Groningen
Heidelberg University
North Carolina State University
Leiden University

Research output: Contribution to journal › Article › peer-review

346 Citations (Scopus)

Abstract

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 × 10^-7 for rs2715148 and 1.2 × 10^-6 for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 × 10^-8 for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

Original language	English
Pages (from-to)	359-375
Number of pages	17
Journal	Molecular Psychiatry
Volume	14
Issue number	4
DOIs	https://doi.org/10.1038/mp.2008.125
Publication status	Published - 9 Dec 2008
Externally published	Yes

Keywords

Genome-wide association
Major depressive disorder
Netherlands study of depression and anxiety
Netherlands twin registry

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10.1038/mp.2008.125

Cite this

Sullivan, P. F., De Geus, E. J. C., Willemsen, G., James, M. R., Smit, J. H., Zandbelt, T., Arolt, V., Baune, B. T., Blackwood, D., Cichon, S., Coventry, W. L., Domschke, K., Farmer, A., Fava, M., Gordon, S. D., He, Q., Heath, A. C., Heutink, P., Holsboer, F., ... Penninx, B. W. J. H. (2008). Genome-wide association for major depressive disorder: A possible role for the presynaptic protein piccolo. Molecular Psychiatry, 14(4), 359-375. https://doi.org/10.1038/mp.2008.125

@article{8073ba550edb414b9ae96433a2015d22,

title = "Genome-wide association for major depressive disorder: A possible role for the presynaptic protein piccolo",

abstract = "Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 × 10-7 for rs2715148 and 1.2 × 10-6 for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 × 10-8 for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.",

keywords = "Genome-wide association, Major depressive disorder, Netherlands study of depression and anxiety, Netherlands twin registry",

author = "Sullivan, \{P. F.\} and \{De Geus\}, \{E. J.C.\} and G. Willemsen and James, \{M. R.\} and Smit, \{J. H.\} and T. Zandbelt and V. Arolt and Baune, \{B. T.\} and D. Blackwood and S. Cichon and Coventry, \{W. L.\} and K. Domschke and A. Farmer and M. Fava and Gordon, \{S. D.\} and Q. He and Heath, \{A. C.\} and P. Heutink and F. Holsboer and Hoogendijk, \{W. J.\} and Hottenga, \{J. J.\} and Y. Hu and M. Kohli and D. Lin and S. Lucae and MacIntyre, \{D. J.\} and W. Maier and McGhee, \{K. A.\} and P. McGuffin and Montgomery, \{G. W.\} and Muir, \{W. J.\} and Nolen, \{W. A.\} and N{\"o}then, \{M. M.\} and Perlis, \{R. H.\} and K. Pirlo and D. Posthuma and M. Rietschel and P. Rizzu and A. Schosser and Smit, \{A. B.\} and Smoller, \{J. W.\} and Tzeng, \{J. Y.\} and \{Van Dyck\}, R. and M. Verhage and Zitman, \{F. G.\} and Martin, \{N. G.\} and Wray, \{N. R.\} and Boomsma, \{D. I.\} and Penninx, \{B. W.J.H.\}",

year = "2008",

month = dec,

day = "9",

doi = "10.1038/mp.2008.125",

language = "English",

volume = "14",

pages = "359--375",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

number = "4",

}

Sullivan, PF, De Geus, EJC, Willemsen, G, James, MR, Smit, JH, Zandbelt, T, Arolt, V, Baune, BT, Blackwood, D, Cichon, S, Coventry, WL, Domschke, K, Farmer, A, Fava, M, Gordon, SD, He, Q, Heath, AC, Heutink, P, Holsboer, F, Hoogendijk, WJ, Hottenga, JJ, Hu, Y, Kohli, M, Lin, D, Lucae, S, MacIntyre, DJ, Maier, W, McGhee, KA, McGuffin, P, Montgomery, GW, Muir, WJ, Nolen, WA, Nöthen, MM, Perlis, RH, Pirlo, K, Posthuma, D, Rietschel, M, Rizzu, P, Schosser, A, Smit, AB, Smoller, JW, Tzeng, JY, Van Dyck, R, Verhage, M, Zitman, FG, Martin, NG, Wray, NR, Boomsma, DI & Penninx, BWJH 2008, 'Genome-wide association for major depressive disorder: A possible role for the presynaptic protein piccolo', Molecular Psychiatry, vol. 14, no. 4, pp. 359-375. https://doi.org/10.1038/mp.2008.125

TY - JOUR

T1 - Genome-wide association for major depressive disorder

T2 - A possible role for the presynaptic protein piccolo

AU - Sullivan, P. F.

AU - De Geus, E. J.C.

AU - Willemsen, G.

AU - James, M. R.

AU - Smit, J. H.

AU - Zandbelt, T.

AU - Arolt, V.

AU - Baune, B. T.

AU - Blackwood, D.

AU - Cichon, S.

AU - Coventry, W. L.

AU - Domschke, K.

AU - Farmer, A.

AU - Fava, M.

AU - Gordon, S. D.

AU - He, Q.

AU - Heath, A. C.

AU - Heutink, P.

AU - Holsboer, F.

AU - Hoogendijk, W. J.

AU - Hottenga, J. J.

AU - Hu, Y.

AU - Kohli, M.

AU - Lin, D.

AU - Lucae, S.

AU - MacIntyre, D. J.

AU - Maier, W.

AU - McGhee, K. A.

AU - McGuffin, P.

AU - Montgomery, G. W.

AU - Muir, W. J.

AU - Nolen, W. A.

AU - Nöthen, M. M.

AU - Perlis, R. H.

AU - Pirlo, K.

AU - Posthuma, D.

AU - Rietschel, M.

AU - Rizzu, P.

AU - Schosser, A.

AU - Smit, A. B.

AU - Smoller, J. W.

AU - Tzeng, J. Y.

AU - Van Dyck, R.

AU - Verhage, M.

AU - Zitman, F. G.

AU - Martin, N. G.

AU - Wray, N. R.

AU - Boomsma, D. I.

AU - Penninx, B. W.J.H.

PY - 2008/12/9

Y1 - 2008/12/9

N2 - Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 × 10-7 for rs2715148 and 1.2 × 10-6 for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 × 10-8 for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

AB - Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 × 10-7 for rs2715148 and 1.2 × 10-6 for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 × 10-8 for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

KW - Genome-wide association

KW - Major depressive disorder

KW - Netherlands study of depression and anxiety

KW - Netherlands twin registry

UR - https://www.scopus.com/pages/publications/62849128600

U2 - 10.1038/mp.2008.125

DO - 10.1038/mp.2008.125

M3 - Article

C2 - 19065144

AN - SCOPUS:62849128600

SN - 1359-4184

VL - 14

SP - 359

EP - 375

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 4

ER -

Genome-wide association for major depressive disorder: A possible role for the presynaptic protein piccolo

Abstract

Keywords

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