ENIGMA OCD working group Teleconference 22 nd of

ENIGMA OCD working group Teleconference 22 nd of May 2015 1 PM GMT (Greenwich Mean Time) Amsterdam/Barcelona/Berlin/Milan/Munich/Rome/Zurich 3 PM Sao Paulo 10 AM Tokyo/Kyoto/Seoul 10 PM Cape Town 3 PM Los Angeles 6 AM New York/Toronto/Michigan/Boston 9 AM Bangalore 6. 30 PM

Agenda 1. 2. 3. 4. 5. 6. 7. 8. Status subcortical meta-analysis Preliminary results subcortical meta-analysis Planning subcortical meta-analysis Future plans q Planning cortical meta-analysis q Secondary research proposals q Mega analysis Hibar et al. IOCDFGC-ENIGMA 1 paper Status grants and new grant opportunities Status GWAS (Jim/Carol) Future meetings Please, send me (oa. vandenheuvel@vumc. nl) an email as soon as your site is‘online’, with the name of the person representing the site during the TC. Take care of the quality of the TC: (un)mute your line by pressing 6!!

Agenda 1. Status subcortical meta-analysis q 2. 3. 4. Preliminary results meta-analysis Planning subcortical meta-analysis Future plans q q q 5. 6. 7. 8. Status per site and overall overview Planning cortical meta-analysis Secondary research proposals Mega analysis Hibar et al. IOCDFGC-ENIGMA 1 paper Status grants and new grant opportunities Status GWAS (Jim/Carol) Future meetings

Current status per site Please, check whether the information is correct and let us know whether the planning (see slide 35) is feasible for your site.

Arnold (CAN) Analyses performed by Soreni(USA) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø quality check Ø please, proceed a. s. a. p. ! DNA material status • Part of the genotyping in house done/ part of the DNA samples are with Jim

Benedetti (ITA) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • DNA samples not sent, still to discuss how to proceed (please contact Jim)

Beucke (DEU) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø please send statistical analyses Ø waiting for clinical data (done by June 1) DNA material status • No DNA samples

Cheng (CHN) Analyses now performed by van den Heuvel (NLD) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø data is being quality checked (Vumc) Ø Waiting for clinical data file (done within 2 wks) DNA material status • Difficulties in transport of DNA samples

Denys (NLD) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • Samples sent to the Broad

Fitzgerald (USA) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • DNA samples partially at Sick. Kids/Jim

Gruner (USA) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • DNA samples sent to Jim

van den Heuvel (NLD) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • DNA samples sent to the Broad/Jim

Hoexter (BRA) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • DNA samples not send yet, will probably be send to Jim

Huyser (NLD) Analyses performed by van den Heuvel (NLD) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • No DNA samples

Koch (DEU) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • No DNA samples

Kwon (KOR) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • DNA samples sent to the Broad

Lazaro (ESP) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • DNA samples sent to the Broad

Mataix-Cols (SWE) Analyses performed by van den Heuvel (NLD) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • No DNA samples

Menchon (ESP) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • DNA samples sent to the Broad

Nakamae (JPN) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • No DNA samples

Nakao (JPN) Analyses performed by van den Heuvel (NLD) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø data is being quality checked (Vumc) Ø waiting for clinical data file, please send a. s. a. p DNA material status • Please update us regarding your DNA samples!!!

Reddy (IND) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø quality checking Ø please proceed a. s. a. p. ! (expected to be done by May 29) DNA material status • Difficulties in transport of DNA samples

Rosenberg (USA) Analyses to be performed by van den Heuvel (NLD) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø preparing data transfer to VUmc Amsterdam (dependent on transfer speed not feasible anymore to include in first subcortical metaanalysis, but big sample of pediatric OCD, thus relevant to try) DNA material status • DNA samples partially at Sick. Kids/Jim

Simpson (USA) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • Small N, still to be discussed with Jim

Soreni (USA) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø quality checking data, please proceed a. s. a. p. ! DNA material status • DNA samples partially at Sick. Kids/Jim

Spalletta (ITA) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • DNA samples sent to the Broad

Stein (ZAF) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • DNA samples sent to Jim

Tolin (USA) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • No DNA samples

Walitza (CHE) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • DNA samples sent to Jim

Wang (CHN) Memorandum of understanding Putamen/pallidum images Histograms + Summarystats R statistical output Current status Ø FINISHED subcortical analyses DNA material status • Difficulties in transport of DNA samples

Memorandum of Understanding Arnold Benedetti Beucke Cheng Denys Fitzgerald Gruner van den Heuvel Hoexter Huyser Koch Kwon Lazaro Mataix-Cols Menchon Nakamae Nakao Reddy Rosenberg Simpson Soreni Spalletta Stein Tolin Walitza Wang

Have sent putamen/pallidum images Arnold Benedetti Beucke Cheng Denys Fitzgerald Gruner van den Heuvel Hoexter Huyser Rosenberg Koch Kwon Lazaro Mataix-Cols Menchon Nakamae Nakao Reddy Simpson Soreni Spalletta Stein Tolin Walitza Wang

First instructions Histograms & Summarystats Arnold Nakao Cheng Reddy Rosenberg Soreni Finished: Benedetti Huyser Beucke Koch Denys Kwon Fitzgerald Lazaro Gruner Mataix-Cols van den Heuvel Menchon Hoexter Nakamae Nakao Simpson Spalletta Tolin Stein Walitza Wang

Second instructions R statistical analyses Arnold Beucke Cheng Nakao Reddy Rosenberg Soreni Finished: Benedetti Koch Denys Kwon Fitzgerald Lazaro Gruner Nakamae van den Heuvel Mataix-Cols Hoexter Menchon Huyser Simpson Spalletta Stein Tolin Walitza Wang

Overview

Agenda 1. 2. 3. 4. 5. 6. 7. 8. Status subcortical meta-analyses Preliminary results subcortical meta-analysis Planning subcortical meta-analysis Future plans q Planning cortical meta-analysis q Secondary research proposals q Mega analysis Hibar et al. IOCDFGC-ENIGMA 1 paper Status grants and new grant opportunities Status GWAS (Jim/Carol) Future meetings

Preliminary results – Adult samples Pallidum OCD vs HC Effect size (Cohen’s d): 0. 12 P-value uncorrected: 0. 041 Analyses controlled for age, sex and ICV

Preliminary results p Similar effect size for hippocampus (d=0. 13; p=0. 045) n P value indicates trend significance (not corrected for multiple comparisons) Moderator analysis showed no influence of field strength p No age by group interaction p p Similar effect sizes (d=-0. 14; p= 4. 6 x 10 -4) found in hippocampus volume of MDD patients vs HC

Agenda 1. 2. 3. 4. 5. 6. 7. 8. Status subcortical meta-analyses Preliminary results subcortical meta-analysis Planning subcortical meta-analysis Future plans q Planning cortical meta-analysis q Secondary research proposals q Mega analysis Hibar et al. IOCDFGC-ENIGMA 1 paper Status grants and new grant opportunities Status GWAS (Jim/Carol) Future meetings

Planning meta-analysis for the subcortical volumes p p p Remaining sites finished all steps for the subcortical analyses in FS and statistical analyses in R > June 01, 2015 Final run meta-analysis (van den Heuvel/Boedhoe at Vumc) > July 01, 2015 July/August: extra time for additional analyses/checks Discussion on results during TC, August 27, 2015 Draft paper > September 2015 Let’s try to meet these deadlines! Note: We have to set a deadline in order to proceed; it would be great to include all sites, but maybe some sites are not able to make it (it’s a pity for them, but these sites can probably join during next meta-analysis, e. g. cortical meta-analysis).

Agenda 1. 2. 3. 4. Status subcortical meta-analysis Preliminary results subcortical meta-analysis Planning subcortical meta-analysis Future plans q Planning cortical meta-analysis is dependent on the progress of the subcortical meta-analysis, but to be started a. s. a. p. (the recon-all also includes cortical segmentation, so the analyses should take up less time) Secondary research proposals q Mega analysis Hibar et al. IOCDFGC-ENIGMA 1 paper Status grants and new grant opportunities Status GWAS (Jim/Carol) Future meetings q 5. 6. 7. 8.

Agenda 1. 2. 3. 4. 5. 6. 7. 8. Status subcortical meta-analyses Preliminary results subcortical meta-analysis Planning subcortical meta-analysis Future plans q Planning cortical meta-analysis q Secondary research proposals q Mega analysis Hibar et al. IOCDFGC-ENIGMA 1 paper Status grants and new grant opportunities Status GWAS (Jim/Carol) Future meetings

Secondary research proposals p Approved (nobody objected) n p To approve (deadline objection May 22) n p DOMAIN (DTI in OCD Meta-analytic Investigation) – Piras et al Meta analysis of cortical structural covariance network – Yun et al Planned/suggested, but analysis plans not yet submitted: n n Resting state: Carles Soriano-Mas connectomics / graph analyses analysis: Kathrin Koch

Agenda 1. 2. 3. 4. 5. 6. 7. 8. Status subcortical meta-analyses Preliminary results subcortical meta-analysis Planning subcortical meta-analysis Future plans q Planning cortical meta-analysis q Secondary research proposals q Mega analysis Hibar et al. IOCDFGC-ENIGMA 1 paper Status grants and new grant opportunities Status GWAS (Jim/Carol) Future meetings

Database for Me. Ga-analysis p To do: q Ethical approval (a. s. a. p. !) q q p Overall: van den Heuvel Each site: check local procedures Fill Excel sheet clinical data (Premika will send format a. s. a. p. ) Prepare sending data (all, who approved sharing raw data) Based on our experience (OBIC and 1 st year ENIGMA-OCD): building this database will cost a massive amount of work. Therefore, we will use ‘strict’ deadlines for data transfer. Sites that are not able to meet the deadlines might join at later stage / future analyses. So, please, start preparing a. s. a. p. (after receiving instructions)!

Agenda 1. 2. 3. 4. 5. 6. 7. 8. Status subcortical meta-analysis Preliminary results meta-analysis Planning subcortical meta-analysis Future plans Hibar et al. IOCDFGC-ENIGMA 1 paper Status grants and new grant opportunities Status GWAS (Jim/Carol) Future meetings

Hibar et al. (in prep. ) Title: Overlap between gene variants mediating risk for OCD and regional brain volumes (prepared for submission Biol Psychiatry) Authors: The ENIGMA and IOCDF-GC Consortium, Derrek P. Hibar 1, IOCDFGC, ENIGMA 2, Evelyn Stewart 2, 3, 4, Odile A. van den Heuvel 5, David L. Pauls 2, 3, James A. Knowles 6, Dan J. Stein 7, Paul M. Thompson 1* Note: ENIGMA-OCD working group not involved as co-authors, since imaging data was not from ENIGMA-OCD working group (no OCD scans involved in this analysis; genetic data was from IOCDFGC consortium). But: findings are very relevant for replicatiom study in our OCD sample!!

Hibar et al. (in prep. ) p p p ABSTRACT Background: A new collaborative effort between the International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortia was formed to determine if there was evidence that (1) partially overlapping sets of genetic variants are associated with both OCD risk and regional brain volumes (pleiotropy), (2) the direction of a effect a genetic variant has on OCD risk variants is the same as its effect on regional brain volumes (concordance), and (3) genetic variants associated with specific brain volumes are significantly associated with OCD risk. Methods: We used SNP Effect Concordance Analysis (SECA) to examine 6, 946, 379 SNPs that passed quality control from a recent large-scale GWAS of OCD (including 1, 465 cases, 5, 557 controls, and 299 trios), and recent genome-wide analyses of eight subcortical brain volumes (in 13, 171 subjects). We determined the extent of genetic overlap between volume-associated SNPs and genetic variants associated with OCD risk. Results: There was significant concordance between OCD risk variants and variants associated with greater nucleus accumbens (P = 2. 0 x 10 -4) and putamen volumes (P = 8. 0 x 10 -4). One variant influencing putamen volume (rs 149154047; q=0. 0375), one variant influencing amygdala volume (rs 534371; q=0. 00626) and two variants influencing thalamus volume (rs 11872098; q=0. 00687 and rs 116331752; q=0. 0374) were significantly associated with the risk for developing OCD, using conditional FDR. Conclusion: These data are largely consistent with current neurocircuitry models of OCD, which have focused on the importance of fronto-striatal circuitry. Variants in the DLGAP 1 gene (rs 11872098) are associated with both thalamic volume and OCD risk, in line with the hypothesized role of altered glutamatergic signaling in OCD.

Agenda Status subcortical meta-analysis Preliminary results meta-analysis Planning subcortical meta-analysis Future plans Hibar et al. IOCDFGC-ENIGMA 1 paper Status grants and new grant opportunities 1. 2. 3. 4. 5. 6. Pending: Carles Soriano-Mas (OCD foundation) 2. Pending: Fabrizio Piras (OCD foundation + national grant) 3. Pending: Paul Arnold 4. Planned: Blair Simpson (NIH-grant for LMICs) 5. Ideas: ? ? Note: feel free to submit also personal grants including ENIGMA-OCD data (but please, propose/discuss plans prior to submission to prevent overlap with other analysis plans) 1. 7. 8. Status GWAS (Jim/Carol) Future meetings

Agenda 1. 2. 3. 4. 5. 6. 7. Status subcortical meta-analysis Preliminary results meta-analysis Planning subcortical meta-analysis Future plans Hibar et al. IOCDFGC-ENIGMA 1 paper Status grants and new grant opportunities Status GWAS (Jim/Carol) 1. 2. 8. Jim/Carol, could you please send overview of database and planning prior to TC? All: please, let us (Premika/me) know what the status is of your DNA (material sent? If so to where (Broad or Jim Knowles? ), material pending genotyping? material genotyped/received back? ) Future meetings

Agenda 7. Status subcortical meta-analyses Preliminary results subcortical meta-analysis Planning subcortical meta-analysis Future plans Hibar et al ENIGMA paper Status grants status GWAS 8. future meetings 1. 2. 3. 4. 5. 6. Ø ENIGMA working group PI’s - June 2015: ENIGMA working group PI’s meeting, prior to HBM, Hawaii Ø ENIGMA OCD working group members - HBM 2015, Hawaii, June 14 -18 Please, email me to inform me about your conference plans, so that I can plan an informal meeting (as we did in Toronto last week)

webpage See previous email for password (May 6). p http: //enigma. ini. usc. edu/ongoing/enigma -ocd-working-group/enigma-ocd-members -page/ p