Skip to main content Accessibility help
×
Home
Hostname: page-component-5bf98f6d76-sglwb Total loading time: 0.751 Render date: 2021-04-20T16:03:58.497Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "metricsAbstractViews": false, "figures": false, "newCiteModal": false, "newCitedByModal": true }

Genome-Wide Significance for PCLO as a Gene for Major Depressive Disorder

Published online by Cambridge University Press:  25 May 2017

Hamdi Mbarek
Affiliation:
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Yuri Milaneschi
Affiliation:
Department of Psychiatry, Amsterdam Public Health Research Institute, VU University Medical Center/GGz inGeest, Amsterdam, the Netherlands
Jouke-Jan Hottenga
Affiliation:
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Lannie Ligthart
Affiliation:
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Eco J. C. de Geus
Affiliation:
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Erik A. Ehli
Affiliation:
Avera Institute for Human Genetics, Sioux Falls, South Dakota, USA
Gonneke Willemsen
Affiliation:
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Gareth E. Davies
Affiliation:
Avera Institute for Human Genetics, Sioux Falls, South Dakota, USA
Jan H. Smit
Affiliation:
Department of Psychiatry, Amsterdam Public Health Research Institute, VU University Medical Center/GGz inGeest, Amsterdam, the Netherlands
Dorret I. Boomsma
Affiliation:
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Brenda W. J. H. Penninx
Affiliation:
Department of Psychiatry, Amsterdam Public Health Research Institute, VU University Medical Center/GGz inGeest, Amsterdam, the Netherlands
Corresponding

Abstract

In 2009, the first genome-wide association study (GWAS) for major depressive disorder (MDD) highlighted an association with PCLO locus on chromosome 7, although not reaching genome-wide significance level. In the present study, we revisited the original GWAS after increasing the overall sample size and the number of interrogated SNPs. In an analysis comparing 1,942 cases with lifetime diagnosis of MDD and 4,565 controls, PCLO showed a genome-wide significant association with MDD at SNP (rs2715157, p = 2.91 × 10−8) and gene-based (p = 1.48 × 10−7) level. Our results confirm the potential role of the PCLO gene in MDD, which is worth further replication and functional studies.

Type
Articles
Copyright
Copyright © The Author(s) 2017 

In 2009, as part of the Genetic Association Information Network (GAIN) initiative, we published (Sullivan et al., Reference Sullivan, de Geus, Willemsen, James, Smit, Zandbelt and Penninx2009) the first genome-wide association study (GWAS) for major depressive disorder (MDD). The participants were assembled from two large Dutch cohorts: the Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Registry (NTR). A comparison between 1,738 cases with lifetime diagnosis of DSM-IV MDD and 1,802 screened controls highlighted a signal overlapping the region of PCLO gene, although variants identified did not reach genome-wide significance. Importantly, our result received strong support (though not reaching formal significance) from Australian data similarly ascertained from a population twin registry (Sullivan et al., Reference Sullivan, de Geus, Willemsen, James, Smit, Zandbelt and Penninx2009). Based on the promising role of PCLO encoding a cytoskeletal protein located in the presynaptic active zone, the original finding was followed by replication efforts, with positive (Hek et al., Reference Hek, Mulder, Luijendijk, van Duijn, Hofman, Uitterlinden and Tiemeier2010) and negative (Verbeek et al., Reference Verbeek, Bevova, Bochdanovits, Rizzu, Bakker, Uithuisje and Heutink2013) results. In the present study, we revisited the original GWAS after introducing important improvements. The overall sample size was almost doubled, adding newly genotyped participants from the original cohorts, consisting mainly of a large number of controls carefully screened using several sources of information including longitudinal assessments and family history (Boomsma et al., Reference Boomsma, Willemsen, Sullivan, Heutink, Meijer, Sondervan and Penninx2008). The number of interrogated SNPs was increased by re-genotyping the majority of participants on a newer array and by imputing variants with a denser reference panel (1,000 Genomes Phase 3).

The present sample consisted of 6,507 participants (63.1% females) of European ancestry from NESDA and NTR. Lifetime MDD diagnoses according to DSM-IV were ascertained using the Composite Interview Diagnostic Instrument. Healthy controls were screened based on absence of any lifetime psychiatric disorder (NESDA), no report of MDD, no known first-degree relatives with MDD, and a low factor score based on a multivariate analysis of depressive complaints, anxiety, neuroticism, and somatic anxiety (Boomsma et al., Reference Boomsma, Beem, van den Berg, Dolan, Koopmans, Vink and Slagboom2000). After applying stringent quality control criteria (Supplementary Methods), we performed a GWAS comparing 1,942 cases and 4,565 controls, adjusting for gender and 10 ancestry-informative principal components. Family structure was taken into account using a sandwich estimator implemented in Plink.

The estimated LD score regression intercept was 1.03, suggesting no appreciable inflation of the test statistics attributable to unaccounted stratification (Figure S1). The analysis identified 17 genome-wide significant SNPs (p < 5 × 10−8; Figure 1) spanning the PCLO gene on chromosome 7 with rs2715157 emerging as the SNP most significantly associated with MDD (p = 2.91 × 10−8); its minor allele (A) was negatively associated with MDD (OR = 0.79). The PCLO lead SNP identified in the original GWAS, rs2715148 showed the same effect size as in the original analysis but was now genome-wide significantly associated with MDD (p = 3.89 × 10−8; OR = 0.79). Similarly, the non-synonymous coding SNP rs2522833 reported the same effect size of the original GWAS but a smaller p value (OR = 1.26, p = 8.29 × 10−8). These SNPs were highly correlated with rs2715157 (r 2 > 0.8; Figure 2). Furthermore, in silico functional annotation of the top SNPs showed possible functional effects. The PCLO SNP rs2715157 alters the sequence of six protein-binding motifs including Pou3f2, indicating a possible effect on the activation of corticotrophin releasing hormone. It also bound to the P300 protein known to regulate gene transcription. SNPs rs2751161 and rs2522835 were contained in a DNase I hypersensitive site suggesting open chromatin, although they did not alter any of the transcription factor binding sites present in the promoter flanking region. Together, these data indicate these SNPs might have direct functional roles (Table S1). Finally, p values of analyzed SNPs were used to perform a gene-based test (Supplementary Methods), and PCLO showed a significant association with MDD (p = 1.48 × 10−7), even considering a stringent multiple comparison adjustment accounting for 20,000 genes (p = 2.5 × 10−6).

Note: EAF = effect allele frequency; OR = odds ratio; 95% CI = 95% confidence interval. aSNP positions are according to NCBI Human Genome Build 37.

FIGURE 1 A. Genome-wide association results for MDD in NTR-NESDA cohorts. The y axis denotes the -log10 (p value) for association. The x axis gives the physical position of SNPs across the genome. The red line indicates the threshold of genome-wide significance p < 5 × 10−8, and the blue line indicates the threshold of p < 5 × 10−5. B. Genome-wide significant loci in the GWAS for MDD in NTR-NESDA cohorts.

Note: Mb = megabases.

FIGURE 2 Regional association plot of PCLO region. The -log10 p values (y axis) of the SNPs are shown according to their chromosomal positions (x axis). The estimated recombination rates from the 1,000 Genomes Project March 2012 release are shown as blue lines, and the genomic locations of genes within the regions of interest in the NCBI Build 37 human assembly are shown as arrows. SNP color represents LD with the most highly associated SNP. The figure was created with LocusZoom (http://csg.sph.umich.edu/locuszoom/).

These findings provide evidence for an association between the PCLO gene and MDD that now clearly reaches genome-wide significance. An important factor was the increase in sample size. Indeed, the effect size detected for SNPs present in both the original and current analyses were exactly the same, but the improved precision in their estimation impacted the test significance. Allele frequencies were also the same for SNPs present in both analyses, suggesting no probable effect on results due to technical differences between the genotyping platforms used in the two GWASs. Nevertheless, imputation allowed us to examine additional SNPs in the same LD block previously not included.

It is important to note that the effectiveness of sample size increase may have been amplified by the clinical homogeneity of the sample and the detailed phenotyping procedure. Recently, the assembling of massive samples has enabled the success of GWAS for depression (Hyde et al., Reference Hyde, Nagle, Tian, Chen, Paciga, Wendland and Winslow2016; Okbay et al., Reference Okbay, Baselmans, De Neve, Turley, Nivard, Fontana and Cesarini2016), overcoming the problematic phenotypic heterogeneity of this trait. Nevertheless, large collaborative studies clearly identified substantial heterogeneity among different MDD datasets as indexed by cross-dataset SNP-correlations smaller than one (Lee et al., Reference Lee, Ripke, Neale, Faraone, Purcell, Perlis and Wray2013), possibly indicating the presence of dataset specific variants. Therefore, collecting a larger sample size, although on a smaller scale, in more homogeneous populations still constitutes a valuable complementary effort aimed at clarifying specific genetic signals that might be overshadowed by the heterogeneity arising from the addition of each new dataset in meta-analytic studies.

To conclude, in our current genome-wide study of MDD, we found confirming evidence of a genome-wide significant association with the PCLO gene. Our findings, together with previous biological evidence (Ahmed et al., Reference Ahmed, Chioza, Rajab, Schmitz-Abe, Al-Khayat, Al-Turki and Mochida2015; Waites et al., Reference Waites, Leal-Ortiz, Andlauer, Sigrist and Garner2011), suggest the importance of the PCLO gene to MDD, which is worth further replication and functional studies.

Conflict of Interest

None.

Acknowledgments

Netherland Twin Register and Netherlands Study of Depression and Anxiety (NESDA): Funding was obtained from the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants Middelgroot-911-09-032, Spinozapremie 56-464-14192, Geestkracht program of the Netherlands Organization for Health Research and Development (ZonMW 10-000-1002), Center for Medical Systems Biology (CSMB, NOW Genomics), Genetic influences on stability and change in psychopathology from childhood to young adulthood (ZonMW 912-10-020), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI–NL, 184.021.007), VU University's Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the European Science Council (ERC Advanced, 230374). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health, Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute for Human Genetics, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995).

Supplementary material

To view supplementary material for this article, please visit https://doi.org/10.1017/thg.2017.30

Footnotes

a

These authors contributed equally to this work.

b

These authors contributed equally to this work.

References

Ahmed, M. Y., Chioza, B. A., Rajab, A., Schmitz-Abe, K., Al-Khayat, A., Al-Turki, S., . . . Mochida, G. H. (2015). Loss of PCLO function underlies pontocerebellar hypoplasia type III. Neurology, 84, 17451750.CrossRefGoogle ScholarPubMed
Boomsma, D. I., Beem, A. L., van den Berg, M., Dolan, C. V., Koopmans, J. R., Vink, J. M., . . . Slagboom, P. E. (2000). Netherlands twin family study of anxious depression (NETSAD). Twin Research, 3, 323334.CrossRefGoogle Scholar
Boomsma, D. I., Willemsen, G., Sullivan, P. F., Heutink, P., Meijer, P., Sondervan, D., . . . Penninx, B. W. (2008). Genome-wide association of major depression: Description of samples for the GAIN major depressive disorder study: NTR and NESDA biobank projects. European Journal of Human Genetics, 16, 335342.CrossRefGoogle ScholarPubMed
Hek, K., Mulder, C. L., Luijendijk, H. J., van Duijn, C. M., Hofman, A., Uitterlinden, A. G., & Tiemeier, H. (2010). The PCLO gene and depressive disorders: Replication in a population-based study. Human Molecular Genetics, 19, 731734.CrossRefGoogle ScholarPubMed
Hyde, C. L., Nagle, M. W., Tian, C., Chen, X., Paciga, S. A., Wendland, J. R., . . . Winslow, A. R. (2016). Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nature Genetics, 48, 10311036.CrossRefGoogle ScholarPubMed
Lee, S. H., Ripke, S., Neale, B. M., Faraone, S. V., Purcell, S. M., Perlis, R. H., . . . Wray, N. R. (2013). Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics, 45, 984994.CrossRefGoogle ScholarPubMed
Okbay, A., Baselmans, B. M., De Neve, J. E., Turley, P., Nivard, M. G., Fontana, M. A., . . . Cesarini, D. (2016). Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nature Genetics, 48, 624633.CrossRefGoogle ScholarPubMed
Sullivan, P. F., de Geus, E. J., Willemsen, G., James, M. R., Smit, J. H., Zandbelt, T., . . . Penninx, B. W. (2009). Genome-wide association for major depressive disorder: A possible role for the presynaptic protein piccolo. Molecular Psychiatry, 14, 359375.CrossRefGoogle ScholarPubMed
Verbeek, E. C., Bevova, M. R., Bochdanovits, Z., Rizzu, P., Bakker, I. M., Uithuisje, T., . . . Heutink, P. (2013). Resequencing three candidate genes for major depressive disorder in a Dutch cohort. PLoS One, 8, e79921.CrossRefGoogle Scholar
Waites, C. L., Leal-Ortiz, S. A., Andlauer, T. F., Sigrist, S. J., & Garner, C. C. (2011). Piccolo regulates the dynamic assembly of presynaptic F-actin. Journal of Neuroscience, 31, 1425014263.CrossRefGoogle ScholarPubMed

Mbarek supplementary material

Mbarek supplementary material 1

File 50 KB

Altmetric attention score

Full text views

Full text views reflects PDF downloads, PDFs sent to Google Drive, Dropbox and Kindle and HTML full text views.

Total number of HTML views: 229
Total number of PDF views: 493 *
View data table for this chart

* Views captured on Cambridge Core between 25th May 2017 - 20th April 2021. This data will be updated every 24 hours.

You have Access

Send article to Kindle

To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Genome-Wide Significance for PCLO as a Gene for Major Depressive Disorder
Available formats
×

Send article to Dropbox

To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

Genome-Wide Significance for PCLO as a Gene for Major Depressive Disorder
Available formats
×

Send article to Google Drive

To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

Genome-Wide Significance for PCLO as a Gene for Major Depressive Disorder
Available formats
×
×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *