Time: 6 Am PT/7 Am MT/8 Am CT/9Am ET/2Pm GMT and 3 Pm CET

ENIGMA-MDD Teleconference, 02/09/2016

Time: 6 am PT/7 am MT/8 am CT/9am ET/2pm GMT and 3 pm CET Phone: 888-921-8686 Passcode: 3102675114#

Host: ● Lianne Schmaal

Attendees Present: ● Udo Dannlowski ● Chris Ching ● Nynke Groenewold ● Meng Li ● Chris Whelan ● Sinead Kelly ● Paul Thompson ● Neda Jahanshad ● Laura van Velzen ● Katharina Wittfeld ● Ilya Veer ● Beata Godlewska ● Theo van Erp ● Boris Gutman ● Thomas Frodl ● Dick Veltman ● Benson Irungu ● Philipp Saemann ● Maria Portella ● Liliana Capitao ● Katie Cullen

Business:

1. Update on cortical meta-analysis paper ● Lianne said the paper is still under review at Molecular Psychiatry. She will let the group know if we get a positive response. ● We would like to run a mega-analysis as our next major ENIGMA-MDD project.

2. New sites

● Lianne pointed the group to the PPT slides listing new sites [slides 8 & 9]. These are sites that have joined since we finished the cortical meta-analysis (so were not part of the cortical meta-analysis, but will be included into the mega-analysis and can participate in secondary projects). ● These sites include: ○ Tokyo sample ○ San Francisco adolescent sample ○ Calgary adolescent sample ○ Leiden? => depends on whether they can find someone to process the data etc. ○ Groningen ○ Barcelona ○ China ○ Oxford adolescent sample ○ Minnesota adolescent sample ○ Houston adolescent sample ● New sites will join the ENIGMA MDD mega-analysis project, but are also very welcome (and encouraged) to participate in secondary projects (see agenda point 5 below).

3. Next ENIGMA MDD project: mega-analysis to examine the impact of MDD on brain structural measures across the life span

● The rationale for a mega-analysis is that there are a few metrics we can’t properly investigate using meta-analysis; e.g. the impact of MDD across the lifespan by modeling age effects and their interaction with MDD (which is difficult to do with a meta-analysis, because within a meta-analysis framework we are limited to do the analysis within each sample separately and many groups have limited age ranges). In addition, pooling all data in a mega-analysis will allow examining more complex (3-way) interactions. We will be discussing some of the statistical analysis methods with the Lifespan group - they used high order fractional polynomial regression to assess the effects of age on structural brain measures in a large number of healthy cohorts. We would like to use similar methods in our MDD mega-analysis to look at age effects in MDD patients and healthy controls. We propose to model age effects separately in early age of onset patients and late age of onset patients. In addition, interactions with clinical characteristics such as recurrence status, medication use, severity (HDRS/BDI) etc. will be examined. ● There is no need for sites to share raw scans. All we need for the mega-analysis are the LandRvolumes.csv, CorticalMeasuresENIGMA_ThickAvg.csv, CorticalMeasuresENIGMA_SurfAvg.csv and Covariates.csv files. Lianne has those files from most sites already, but new sites are still working on creating these files. ● Lianne said we have planned a data freeze of April 1st for the mega-analysis. ○ The group had no objections to this deadline. ● Lianne invited the group to send her an email if they have ideas for other covariates for this analysis or if they have any other thoughts on the planned analysis.

5. Update on secondary projects: 5a. Childhood maltreatment (Thomas Frodl) ● Thomas said the first paper is under review at Am J Psych and he is awaiting feedback. ○ He’d like to extend the analysis to cortical volumes. Thomas will write a new proposal for the cortical childhood trauma project. The approved version of that proposal will be circulated to all sites within ENIGMA MDD, so that every site has the chance to participate (also new sites). ○ If you have any data on childhood trauma, please email Thomas at [email protected].

5b. Suicidality (Miguel Renteria) ● Lianne said that Miguel is temporarily working the UK. She asked Miguel for an update on the subcortical suicidality paper but she has yet to receive a response.

5c. DTI (Sinead Kelly & Laura van Velzen) ● Sinead said that five sites have completed the processing using the ENIGMA-DTI protocols so far. ○ CODE have 4 of 5 sites complete. ○ Magdeburg expects to complete their analysis by the end of the week. ○ Awaiting updates from QTIM, MPIP, Barcelona (Maria was in touch) ○ Laura is processing the NESDA and MOTAR cohorts as well as the China cohort and is going to process the San Francisco sample as well. ○ A few sites have completed the sample characteristics / demographics spreadsheet. Please complete this spreadsheet if you have not done so already (Sinead will send around the link to the form via email again). ○ Before Christmas, MUNSTER, STANFORD, SYDNEY and DUBLIN completed the protocols. We used this data to run a preliminary analysis for an OHBM abstract. ■ We found a large, significant effect size for FA in MDD patients in the corpus callosum (effects were highest in the body and genu of the corpus callosum). ■ White matter microstructural changes in the CC have previously been implicated in MDD. ○ Future goals: We hope all sites to be finished by the end of this month. We will follow up with these sites shortly. ○ When all sites have finished processing, we will discuss clinical covariates to include in our statistical analysis. We will also plan a mega-analysis. ○ If you’d like to participate, contact Sinead at [email protected] and [email protected]

5d. Shape (Boris Gutman and Sean Hatton) ● Boris said 11 sites have signed up to the subcortical shape project. ○ 5 sites are currently running the protocols. ○ Slide 22 gives a detailed progress report of each subgroup. ○ The group hopes to get everything finished by early May. ○ Preliminary results (submitted to OHBM 2016) are detailed on slide 24. There was a hit in the left pallidum and left thalamus as well as an age by diagnosis effect in the right caudate. ○ If you’d like to participate, contact Boris at [email protected]

5e. Hippocampal subfields (Philipp Saemann)

● Philipp said the group submitted a preliminary analysis to OHBM 2016 based on his local MPIP sample (see slide 28). He will send around the protocols for processing the data to obtain the subfields volumes and to perform the QA very soon. 9 sites have indicated to be willing to participate (see slide 26). New sites can still join. If you would like to participate, contact [email protected]

5f. Developing a common metric of severity

● There are 2 initiatives with regard to defining severity in ENIGMA MDD: 1. Developing a common metric of different severity questionnaires – Felix Fischer Lianne said the first attempt was not very successful, but Felix is going to give it another try. He will follow-up with sites from which he still needs data. 2. Severity defined through clinical characteristics – Henrik Walter, Bernard Baune, Ilya Veer and others Henrik Walter and others are working on a secondary project proposal that aims to look at severity defined in another way; e.g. through recurrence, age of onset etc. There are a few ideas for this, which will be summarized in an official project proposal. Ilya indicated that Lianne can expect this proposal in the next couple of months.

6. Imaging Genetics

● Lianne said we are currently collecting information on the availability of DNA in each sample, the type of DNA, the status of DNA sample (genotyped/not yet genotyped) etc. Lianne has a rough idea of which sites have DNA samples, but we would like to collect this information in a harmonized and organized way across disease working groups for the purpose of exploring options for genotyping samples that have not been genotyped yet for free or a reduced rate (which might be easier if we have a bigger number of samples) and for potential future cross-disorder imaging genetics analysis plans (which will always be discussed with the ENIGMA MDD PIs first). ● If you have yet to complete the form, please do so at the following link: ○ https://docs.google.com/forms/d/1ZBIptTJCq7ey1dqjR4wqnZte2g8x1udSnJ_ibyvqYFU/viewfor m?usp=send_form ● If you have DNA samples but they have yet to be genotyped, there may be some options for free genotyping (or genotyping at a reduced price). ● Once we have this information, we can start running imaging genetics analyses. There are plans to develop polygenic risk score ‘cookbooks’, i.e. protocols to create polygenic risk scores for e.g. MDD, SZ, BD, or for subcortical and cortical structural measures, that can be used ENIGMA-wide (by different disease working groups). We can discuss different analysis plans - e.g. polygenic risk scores, SNPs, GWAS. But we want to have an overview of the available DNA data and have all samples genotyped first, before any plans are made. ● Philipp said that people could contact him if they have any questions for genotyping options.

7. Upcoming Conferences: SOBP, OHBM, ISAD

● Lianne reminded the group of upcoming conferences, including: ○ SOBP 2016, Altanta, May 12-14 ○ OHBM 2016, Geneva, June 26-30 ○ ISAD/ISBD 2016, Amsterdam, July 13-16 ● We have two symposia at SOBP. One is the ENIGMA Lifespan symposium (here we will present results from ENIGMA-MDD mega-analysis on the effects of MDD on brain structure across the life span) and the other is the ENIGMA psychiatric symposium (cortical, DTI, shape results from the MDD and SZ working groups will all be presented). ● We have submitted an abstract for OHBM. ● An abstract submitted by Chris Davey (from our Melbourne site) on imaging in adolescent depression, in which Chris, Lianne and Tiffany Ho (from our San Francisco site) was accepted by the ISAD conference. ● If you have plans to attend these conferences, please email Lianne so she can plan some formal or informal meetings during the conferences.