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The effect of FTO rs9939609 on major depression differs across MDD subtypes

Molecular Psychiatry volume 19, pages 960–962 (2014)Cite this article

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Recently, Samaan et al.1 reported in this journal that the fat mass and obesity-associated protein (FTO) rs9939609 A variant was associated with a lower risk of major depressive disorder (MDD) independently from BMI. However, clinical heterogeneity may contribute to variability of results in association studies investigating the biologic and genetic underpinnings of MDD. Using data from the Netherlands Study of Depression and Anxiety (NESDA) we showed2 in a previous issue of the journal that depressed patients can be divided using data-driven techniques into a ‘typical’ (termed also ‘melancholic’) and an ‘atypical’ subtype differentiated mainly by the direction of change in vegetative symptoms (that is, appetite, weight and sleep) and associated with distinct biological correlates, pointing to a partially distinct pathophysiological and genetic liability. Therefore, considering our prior observations that obesity and increased appetite are more prevalent in atypical depression, and obesity rates are not different or even less prevalent as compared with controls in typical depression,2, 3, it can be expected that the FTO variant shows different associations across MDD subtypes. As an exemplification of our hypothesis, we performed the same association test between rs9939609 and MDD as in the paper of Samaan et al.1 In addition, we explored whether this association differed across clinical subtypes.

Our sample consisted of 4350 unrelated participants (42.0±14.1 years of age, 63.6% females) of European ancestry from the NESDA4 (1544 cases and 336 controls) and from the Netherlands Twin Registry5 (2470 controls). Genotyping and imputation methods and QC checks have been extensively detailed elsewhere.6 Briefly, genotyping has been subsequently performed on multiple chip platforms in (partially overlapping) different subsets of the total sample (Affymetrix-Perlegen 5.0, Illumina 370 K, Illumina 660 K, Illumina Omni 1 M and Affymetrix 6.0) and data were imputed using the 1000 Genomes phase 1 INTEGRATED RELEASE version 3 ALL panel.7 rs9939609 was typed in some of the panels used for imputation and all post-imputation QC criteria were met; r2hat value was 0.99, indicating an almost perfect correlation between the imputed genotype and its true underlying genotype. Minor allele frequency was 0.38. The diagnosis of lifetime and/or current MDD according to DSM-IV was ascertained using the Composite Interview Diagnostic Instrument.8 Among 1178 cases with available symptom-level data, depressive symptoms were used as indicator variables in a latent class analyses approach as previously described;2 we identified two classes characterized by high severity, typical (20%) and atypical (21.7%), and a class of moderate severity (58.3%). Height and weight were measured to calculate body mass index (BMI) in kg m−2. The association between rs9939609 (additive model) and different outcomes were tested using linear and (multinomial) logistic regressions adjusting for age, sex and population stratification (three principal components). Analyses were performed in SAS (v. 9.2, SAS Institute, Cary, NC, USA) and R (v. 3.0.1, R Project for Statistical Computing).

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Acknowledgements

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, NWO 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, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995).

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Authors and Affiliations

  1. Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands

    Y Milaneschi, F Lamers & B W J H Penninx

  2. Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands

    H Mbarek, J-J Hottenga & D I Boomsma

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  1. Y Milaneschi
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  2. F Lamers
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  3. H Mbarek
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  4. J-J Hottenga
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  5. D I Boomsma
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  6. B W J H Penninx
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Correspondence to Y Milaneschi.

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Milaneschi, Y., Lamers, F., Mbarek, H. et al. The effect of FTO rs9939609 on major depression differs across MDD subtypes. Mol Psychiatry 19, 960–962 (2014). https://doi.org/10.1038/mp.2014.4

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