A continuum of genetic liability for minor and major depression

E C Corfield, Y Yang, N G Martin, D R Nyholt, E C Corfield, Y Yang, N G Martin, D R Nyholt

Abstract

The recent success of a large genome-wide association (GWA) study-analysing 130 620 major depression cases and 347 620 controls-in identifying the first single-nucleotide polymorphism (SNP) loci robustly associated with major depression in Europeans confirms that immense sample sizes are required to identify risk loci for depression. Given the phenotypic similarity between major depressive disorder (MDD) and the less severe minor depressive disorder (MiDD), we hypothesised that broadening the case definition to include MiDD may be an efficient approach to increase sample sizes in GWA studies of depression. By analysing two large twin pair cohorts, we show that minor depression and major depression lie on a single genetic continuum, with major depression being more severe but not aetiologically distinct from minor depression. Furthermore, we estimate heritabilities of 37% for minor depression, 46% for major depression and 48% for minor or major depression in a cohort of older adults (aged 50-92). However, the heritability of minor or major depression was estimated at 40% in a cohort of younger adults (aged 23-38). Moreover, two robust major depression-risk SNPs nominally associated with major depression in our Australian GWA data set produced more significant evidence for association with minor or major depression. Hence, broadening the case phenotype in GWA studies to include subthreshold definitions, such as MiDD, should facilitate the identification of additional genetic risk loci for depression.

Conflict of interest statement

The authors declare no conflict of interest.

References

    1. Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 2000; 157: 1552–1562.
    1. Sullivan PF, de Geus EJ, Willemsen G, James MR, Smit JH, Zandbelt T et al. Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo. Mol Psychiatry 2009; 14: 359–375.
    1. Muglia P, Tozzi F, Galwey NW, Francks C, Upmanyu R, Kong XQ et al. Genome-wide association study of recurrent major depressive disorder in two European case-control cohorts. Mol Psychiatry 2010; 15: 589–601.
    1. Lewis CM, Ng MY, Butler AW, Cohen-Woods S, Uher R, Pirlo K et al. Genome-wide association study of major recurrent depression in the U.K. population. Am J Psychiatry 2010; 167: 949–957.
    1. Rietschel M, Mattheisen M, Frank J, Treutlein J, Degenhardt F, Breuer R et al. Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression. Biol Psychiatry 2010; 68: 578–585.
    1. Shi J, Potash JB, Knowles JA, Weissman MM, Coryell W, Scheftner WA et al. Genome-wide association study of recurrent early-onset major depressive disorder. Mol Psychiatry 2011; 16: 193–201.
    1. Shyn SI, Shi J, Kraft JB, Potash JB, Knowles JA, Weissman MM et al. Novel loci for major depression identified by genome-wide association study of sequenced treatment alternatives to relieve depression and meta-analysis of three studies. Mol Psychiatry 2011; 16: 202–215.
    1. Kohli MA, Lucae S, Saemann PG, Schmidt MV, Demirkan A, Hek K et al. The neuronal transporter gene SLC6A15 confers risk to major depression. Neuron 2011; 70: 252–265.
    1. Bosker FJ, Hartman CA, Nolte IM, Prins BP, Terpstra P, Posthuma D et al. Poor replication of candidate genes for major depressive disorder using genome-wide association data. Mol Psychiatry 2011; 16: 516–532.
    1. Wray NR, Pergadia ML, Blackwood DH, Penninx BW, Gordon SD, Nyholt DR et al. Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned. Mol Psychiatry 2012; 17: 36–48.
    1. Major Depressive Disorder Working Group of the Psychiatric GWAS ConsortiumMajor Depressive Disorder Working Group of the Psychiatric GWAS ConsortiumRipke S Major Depressive Disorder Working Group of the Psychiatric GWAS ConsortiumWray NR Major Depressive Disorder Working Group of the Psychiatric GWAS ConsortiumLewis CM Major Depressive Disorder Working Group of the Psychiatric GWAS ConsortiumHamilton SP Major Depressive Disorder Working Group of the Psychiatric GWAS ConsortiumWeissman MM et al. A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 2013; 18: 497–511.
    1. CONVERGE consortium. Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature 2015; 523: 588–591.
    1. Hyde CL, Nagle MW, Tian C, Chen X, Paciga SA, Wendland JR et al. Identification of 15 genetic loci associated with risk of major depression in individuals of European descent. Nat Genet 2016; 48: 1031–1036.
    1. Visscher PM, Brown MA, McCarthy MI, Yang J. Five years of GWAS discovery. Am J Hum Genet 2012; 90: 7–24.
    1. Okbay A, Baselmans BML, De Neve J-E, Turley P, Nivard MG, Fontana MA et al. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nat Genet 2016; 48: 624–633.
    1. Direk N, Williams S, Smith JA, Ripke S, Air T, Amare AT et al. An analysis of two genome-wide association meta-analyses identifies a new locus for broad depression phenotype. Biol Psychiatry 2016.
    1. Power RA, Tansey KE, Buttenschon HN, Cohen-Woods S, Bigdeli T, Hall LS et al. Genome-wide association for major depression through age at onset stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. Biol Psychiatry 2017; 81: 325–335.
    1. American Psychiatric AssociationDiagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). American Psychiatric Publishing:: Washington, DC, USA, 2013.
    1. American Psychiatric Association.Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR. American Psychiatric Association:: Washington, DC, USA, 2000.
    1. Cuijpers P, Smit F. Subthreshold depression as a risk indicator for major depressive disorder: a systematic review of prospective studies. Acta Psychiatr Scand 2004; 109: 325–331.
    1. Judd LL, Akiskal HS, Paulus MP. The role and clinical significance of subsyndromal depressive symptoms (SSD) in unipolar major depressive disorder. J Affect Disord 1997; 45: 5–18.
    1. Chen LS, Eaton WW, Gallo JJ, Nestadt G, Crum RM. Empirical examination of current depression categories in a population-based study: Symptoms, course, and risk factors. Am J Psychiatry 2000; 157: 573–580.
    1. Rapaport MH, Judd LL, Schettler PJ, Yonkers KA, Thase ME, Kupfer DJ et al. A descriptive analysis of minor depression. Am J Psychiatry 2002; 159: 637–643.
    1. Lewinsohn PM, Klein DN, Durbin EC, Seeley JR, Rohde P. Family study of subthreshold depressive symptoms: Risk factor for MDD? J Affect Disord 2003; 77: 149–157.
    1. Cuijpers P, de Graaf R, van Dorsselaer S. Minor depression: risk profiles, functional disability, health care use and risk of developing major depression. J Affect Disord 2004; 79: 71–79.
    1. Bucholz KK, Heath AC, Madden PAF, Slutske WS, Statham DJ, Dunne MP et al. Drinking in an older population: cross-sectional and longitudinal data from the Australian twin registry. In: Gomberg EL, Hegedus AM, Zucker RA (eds). Alcohol Problems and Aging. National Institutes of Health: Bethesda, MD, USA, 1998, pp 41–62..
    1. Mosing MA, Medland SE, McRae A, Landers JG, Wright MJ, Martin NG. Genetic influences on life span and its relationship to personality: a 16-year follow-up study of a sample of aging twins. Psychosom Med 2012; 74: 16–22.
    1. Goldberg DP, Blackwell B. Psychiatric illness in general practice. A detailed study using a new method of case identification. Br Med J 1970; 1: 439–443.
    1. Bedford A, Deary IJ. The personal disturbance scale (DSSI/sAD): development, use and structure. Pers Individ Dif 1997; 22: 493–510.
    1. Corfield EC, Martin NG, Nyholt DR. Co-occurrence and symptomatology of fatigue and depression. Compr Psychiatry 2016; 71: 1–10.
    1. Heath AC, Howells W, Kirk KM, Madden PA, Bucholz KK, Nelson EC et al. Predictors of non-response to a questionnaire survey of a volunteer twin panel: findings from the Australian 1989 twin cohort. Twin Res 2001; 4: 73–80.
    1. Yang Y, Zhao H, Heath AC, Madden PA, Martin NG, Nyholt DR. Shared genetic factors underlie migraine and depression. Twin Res Hum Genet 2016; 19: 341–350.
    1. Nyholt DR, Gillespie NG, Heath AC, Merikangas KR, Duffy DL, Martin NG. Latent class and genetic analysis does not support migraine with aura and migraine without aura as separate entities. Genet Epidemiol 2004; 26: 231–244.
    1. Reich T, James JW, Morris CA. The use of multiple thresholds in determining the mode of transmission of semi-continuous traits. Ann Hum Genet 1972; 36: 163–184.
    1. Uebersax JS. User Guide for POLYCORR 1.1. (Statistical Methods for Rater Agreement web site). Available from: (accessed on 2007).
    1. Kendler KS. Twin studies of psychiatric illness. Current status and future directions. Arch Gen Psychiatry 1993; 50: 905–915.
    1. Neale M, Cardon L. Methodology for Genetic Studies of Twins and Families. Springer: New York, NY, 1992.
    1. Boker S, Neale M, Maes H, Wilde M, Spiegel M, Brick T et al. OpenMx: an open source extended structural equation modeling framework. Psychometrika 2011; 76: 306–317.
    1. Akaike H. A new look at the statistical model identification. IEEE Trans Automatic Control 1974; 19: 716–723.
    1. Akaike H. Information theory and an extension of the maximum likelihood principle. In: Petrov BN, Csáki F (eds). Second International Symposium on Information Theory; Tsahkadsor, Armenia, USSR. Akadémiai Kiadó: Budapest, 1973, pp 267–281..
    1. Medland SE, Nyholt DR, Painter JN, McEvoy BP, McRae AF, Zhu G et al. Common variants in the trichohyalin gene are associated with straight hair in Europeans. Am J Hum Genet 2009; 85: 750–755.
    1. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
    1. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. A population-based twin study of major depression in women. The impact of varying definitions of illness. Arch Gen Psychiatry 1992; 49: 257–266.
    1. Zeng Y, Navarro P, Xia C, Amador C, Fernandez-Pujals AM, Thomson PA et al. Shared genetics and couple-associated environment are major contributors to the risk of both clinical and self-declared depression. EBioMedicine 2016; 14: 161–167.
    1. Sullivan P. Don't give up on GWAS. Mol Psychiatry 2012; 17: 2–3.
    1. Pearson R, Palmer RH, Brick LA, McGeary JE, Knopik VS, Beevers CG. Additive genetic contribution to symptom dimensions in major depressive disorder. J Abnorm Psychol 2016; 125: 495–501.

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