Skip to main content

Familiality and SNP heritability of age at onset and episodicity in major depressive disorder

  • P. Ferentinos (a1) (a2), A. Koukounari (a3), R. Power (a1), M. Rivera (a1) (a4), R. Uher (a1) (a5), N. Craddock (a6), M. J. Owen (a6), A. Korszun (a7), L. Jones (a8), I. Jones (a6), M. Gill (a9), J. P. Rice (a10), M. Ising (a11), W. Maier (a12), O. Mors (a13), M. Rietschel (a14), M. Preisig (a15), E. B. Binder (a11), K. J. Aitchison (a16), J. Mendlewicz (a17), D. Souery (a18), J. Hauser (a19), N. Henigsberg (a20), G. Breen (a1) (a21), I. W. Craig (a1), A. E. Farmer (a1), B. Müller-Myhsok (a11), P. McGuffin (a1) and C. M. Lewis (a1) (a22)...

Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability).


For investigating familiality, we used 691 families with 2–5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software.


Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity.


AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure 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 or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ 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.

      Familiality and SNP heritability of age at onset and episodicity in 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.

      Familiality and SNP heritability of age at onset and episodicity in 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.

      Familiality and SNP heritability of age at onset and episodicity in major depressive disorder
      Available formats
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (, which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Corresponding author
* Address for correspondence: Dr P. Ferentinos, MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, London SE5 8AF, UK and 2nd Department of Psychiatry, Attikon General Hospital, University of Athens, Athens, Greece. (Email:;
Hide All
Aguiar Ferreira, A, Vasconcelos, AG, Neves, FS, Laks, J, Correa, H (2013). Affective temperaments: familiality and clinical use in mood disorders. Journal of Affective Disorders 148, 5356.
Baethge, C, Schlattmann, P (2004). A survival analysis for recurrent events in psychiatric research. Bipolar Disorders 6, 115121.
Blom, G (1958). Statistical estimates and transformed beta variables. John Wiley and Sons: New York.
Bolker, BM, Brooks, ME, Clark, CJ, Geange, SW, Poulsen, JR, Stevens, MH, White, JS (2009). Generalized linear mixed models: a practical guide for ecology and evolution. Trends in Ecology & Evolution 24, 127135.
Breen, G, Webb, BT, Butler, AW, van den Oord, EJ, Tozzi, F, Craddock, N, Gill, M, Korszun, A, Maier, W, Middleton, L, Mors, O, Owen, MJ, Cohen-Woods, S, Perry, J, Galwey, NW, Upmanyu, R, Craig, I, Lewis, CM, Ng, M, Brewster, S, Preisig, M, Rietschel, M, Jones, L, Knight, J, Rice, J, Muglia, P, Farmer, AE, McGuffin, P (2011). A genome-wide significant linkage for severe depression on chromosome 3: the depression network study. American Journal of Psychiatry 168, 840847.
Carrasco, JL (2010). A generalized concordance correlation coefficient based on the variance components generalized linear mixed models for overdispersed count data. Biometrics 66, 897904.
Carrasco, JL, Jover, L (2003). Estimating the generalized concordance correlation coefficient through variance components. Biometrics 59, 849858.
Carrasco, JL, Jover, L (2005). Concordance correlation coefficient applied to discrete data. Statistics in Medicine 24, 4021–434.
Cohen-Woods, S, Gaysina, D, Craddock, N, Farmer, A, Gray, J, Gunasinghe, C, Hoda, F, Jones, L, Knight, J, Korszun, A, Owen, MJ, Sterne, A, Craig, IW, McGuffin, P (2009). Depression Case Control (DeCC) Study fails to support involvement of the muscarinic acetylcholine receptor M2 (CHRM2) gene in recurrent major depressive disorder. Human Molecular Genetics 18, 15041509.
Dikeos, DG, Papadimitriou, GN, Soldatos, CR (2004). Familial aggregation of suicidal ideation in psychiatric patients: influence of gender. Neuropsychobiology 50, 216220.
Falconer, DS, Mackay, TFC (1996). Ìntroduction to Quantitative Genetics. Pearson Education Ltd: Edinburgh.
Farmer, A, Breen, G, Brewster, S, Craddock, N, Gill, M, Korszun, A, Maier, W, Middleton, L, Mors, O, Owen, M, Perry, J, Preisig, M, Rietschel, M, Reich, T, Jones, L, Jones, I, McGuffin, P (2004). The Depression Network (DeNT) Study: methodology and sociodemographic characteristics of the first 470 affected sibling pairs from a large multi-site linkage genetic study. BMC Psychiatry 4, 42.
Farmer, A, Mahmood, A, Redman, K, Harris, T, Sadler, S, McGuffin, P (2003). A sib-pair study of the Temperament and Character Inventory scales in major depression. Archives of General Psychiatry 60, 490496.
Ferentinos, P, Rivera, M, Ising, M, Spain, SL, Cohen-Woods, S, Butler, AW, Craddock, N, Owen, MJ, Korszun, A, Jones, L, Jones, I, Gill, M, Rice, JP, Maier, W, Mors, O, Rietschel, M, Lucae, S, Binder, EB, Preisig, M, Tozzi, F, Muglia, P, Breen, G, Craig, IW, Farmer, AE, Muller-Myhsok, B, McGuffin, P, Lewis, CM (2014). Investigating the genetic variation underlying episodicity in major depressive disorder: suggestive evidence for a bipolar contribution. Journal of Affective Disorders 155, 8189.
Fisfalen, ME, Schulze, TG, DePaulo, JR Jr., DeGroot, LJ, Badner, JA, McMahon, FJ (2005). Familial variation in episode frequency in bipolar affective disorder. American Journal of Psychiatry 162, 12661272.
Kassem, L, Lopez, V, Hedeker, D, Steele, J, Zandi, P, McMahon, FJ (2006). Familiality of polarity at illness onset in bipolar affective disorder. American Journal of Psychiatry 163, 17541759.
Kendler, KS, Karkowski-Shuman, L (1997). Stressful life events and genetic liability to major depression: genetic control of exposure to the environment? Psychological Medicine 27, 539547.
Kendler, KS, Neale, MC, Kessler, RC, Heath, AC, Eaves, LJ (1992). Familial influences on the clinical characteristics of major depression: a twin study. Acta Psychiatrica Scandinavica 86, 371378.
Kessing, LV, Olsen, EW, Andersen, PK (1999). Recurrence in affective disorder: analyses with frailty models. American Journal of Epidemiology 149, 404411.
Kohli, MA, Lucae, S, Saemann, PG, Schmidt, MV, Demirkan, A, Hek, K, Czamara, D, Alexander, M, Salyakina, D, Ripke, S, Hoehn, D, Specht, M, Menke, A, Hennings, J, Heck, A, Wolf, C, Ising, M, Schreiber, S, Czisch, M, Muller, MB, Uhr, M, Bettecken, T, Becker, A, Schramm, J, Rietschel, M, Maier, W, Bradley, B, Ressler, KJ, Nothen, MM, Cichon, S, Craig, IW, Breen, G, Lewis, CM, Hofman, A, Tiemeier, H, van Duijn, CM, Holsboer, F, Muller-Myhsok, B, Binder, EB (2011). The neuronal transporter gene SLC6A15 confers risk to major depression. Neuron 70, 252265.
Korszun, A, Moskvina, V, Brewster, S, Craddock, N, Ferrero, F, Gill, M, Jones, IR, Jones, LA, Maier, W, Mors, O, Owen, MJ, Preisig, M, Reich, T, Rietschel, M, Farmer, A, McGuffin, P (2004). Familiality of symptom dimensions in depression. Archives of General Psychiatry 61, 468474.
Lai, YC, Huang, MC, Chen, HC, Lu, MK, Chiu, YH, Shen, WW, Lu, RB, Kuo, PH (2013). Familiality and clinical outcomes of sleep disturbances in major depressive and bipolar disorders. Journal of Psychosomatic Research 76, 6167.
Leboyer, M, Bellivier, F, McKeon, P, Albus, M, Borrman, M, Perez-Diaz, F, Mynett-Johnson, L, Feingold, J, Maier, W (1998). Age at onset and gender resemblance in bipolar siblings. Psychiatry Research 81, 125131.
Lee, SH, Yang, J, Goddard, ME, Visscher, PM, Wray, NR (2012). Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood. Bioinformatics 28, 25402542.
Lewis, CM, Ng, MY, Butler, AW, Cohen-Woods, S, Uher, R, Pirlo, K, Weale, ME, Schosser, A, Paredes, UM, Rivera, M, Craddock, N, Owen, MJ, Jones, L, Jones, I, Korszun, A, Aitchison, KJ, Shi, J, Quinn, JP, Mackenzie, A, Vollenweider, P, Waeber, G, Heath, S, Lathrop, M, Muglia, P, Barnes, MR, Whittaker, JC, Tozzi, F, Holsboer, F, Preisig, M, Farmer, AE, Breen, G, Craig, IW, McGuffin, P (2010). Genome-wide association study of major recurrent depression in the U.K. population. American Journal of Psychiatry 167, 949957.
Lin, PI, McInnis, MG, Potash, JB, Willour, V, MacKinnon, DF, DePaulo, JR, Zandi, PP (2006). Clinical correlates and familial aggregation of age at onset in bipolar disorder. American Journal of Psychiatry 163, 240246.
MacKinnon, DF, McMahon, FJ, Simpson, SG, McInnis, MG, DePaulo, JR (1997). Panic disorder with familial bipolar disorder. Biological Psychiatry 42, 9095.
McGirr, A, Alda, M, Seguin, M, Cabot, S, Lesage, A, Turecki, G (2009). Familial aggregation of suicide explained by cluster B traits: a three-group family study of suicide controlling for major depressive disorder. American Journal of Psychiatry 166, 11241134.
McGuffin, P, Knight, J, Breen, G, Brewster, S, Boyd, PR, Craddock, N, Gill, M, Korszun, A, Maier, W, Middleton, L, Mors, O, Owen, MJ, Perry, J, Preisig, M, Reich, T, Rice, J, Rietschel, M, Jones, L, Sham, P, Farmer, AE (2005). Whole genome linkage scan of recurrent depressive disorder from the depression network study. Human Molecular Genetics 14, 33373345.
Mondimore, FM, Zandi, PP, Mackinnon, DF, McInnis, MG, Miller, EB, Crowe, RP, Scheftner, WA, Marta, DH, Weissman, MM, Levinson, DF, Murphy-Ebenez, KP, Depaulo, JR Jr., Potash, JB (2006). Familial aggregation of illness chronicity in recurrent, early-onset major depression pedigrees. American Journal of Psychiatry 163, 15541560.
Muglia, P, Tozzi, F, Galwey, NW, Francks, C, Upmanyu, R, Kong, XQ, Antoniades, A, Domenici, E, Perry, J, Rothen, S, Vandeleur, CL, Mooser, V, Waeber, G, Vollenweider, P, Preisig, M, Lucae, S, Muller-Myhsok, B, Holsboer, F, Middleton, LT, Roses, AD (2010). Genome-wide association study of recurrent major depressive disorder in two European case-control cohorts. Molecular Psychiatry 15, 589601.
O'Mahony, E, Corvin, A, O'Connell, R, Comerford, C, Larsen, B, Jones, R, McCandless, F, Kirov, G, Cardno, AG, Craddock, N, Gill, M (2002). Sibling pairs with affective disorders: resemblance of demographic and clinical features. Psychological Medicine 32, 5561.
PGC (2013). A mega-analysis of genome-wide association studies for major depressive disorder. Molecular Psychiatry 18, 497511.
Potash, JB, Willour, VL, Chiu, YF, Simpson, SG, MacKinnon, DF, Pearlson, GD, DePaulo, JR Jr., McInnis, MG (2001). The familial aggregation of psychotic symptoms in bipolar disorder pedigrees. American Journal of Psychiatry 158, 12581264.
Power, RA, Keers, R, Ng, MY, Butler, AW, Uher, R, Cohen-Woods, S, Ising, M, Craddock, N, Owen, MJ, Korszun, A, Jones, L, Jones, I, Gill, M, Rice, JP, Hauser, J, Henigsberg, N, Maier, W, Zobel, A, Mors, O, Placentino, AS, Rietschel, M, Souery, D, Kozel, D, Preisig, M, Lucae, S, Binder, EB, Aitchison, KJ, Tozzi, F, Muglia, P, Breen, G, Craig, IW, Farmer, AE, Muller-Myhsok, B, McGuffin, P, Lewis, CM (2012). Dissecting the genetic heterogeneity of depression through age at onset. American Journal of Medical Genetics Part B Neuropsychiatric Genetics 159B, 859868.
Power, RA, Wingenbach, T, Cohen-Woods, S, Uher, R, Ng, MY, Butler, AW, Ising, M, Craddock, N, Owen, MJ, Korszun, A, Jones, L, Jones, I, Gill, M, Rice, JP, Maier, W, Zobel, A, Mors, O, Placentino, A, Rietschel, M, Lucae, S, Holsboer, F, Binder, EB, Keers, R, Tozzi, F, Muglia, P, Breen, G, Craig, IW, Muller-Myhsok, B, Kennedy, JL, Strauss, J, Vincent, JB, Lewis, CM, Farmer, AE, McGuffin, P (2013). Estimating the heritability of reporting stressful life events captured by common genetic variants. Psychological Medicine 43, 19651971.
Purcell, S (2002). Variance components models for gene-environment interaction in twin analysis. Twin Research 5, 554571.
Purcell, S, Neale, B, Todd-Brown, K, Thomas, L, Ferreira, MA, Bender, D, Maller, J, Sklar, P, de Bakker, PI, Daly, MJ, Sham, PC (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics 81, 559575.
Purcell, S, Sham, P (2002). Variance components models for gene-environment interaction in quantitative trait locus linkage analysis. Twin Research 5, 572576.
Rietschel, M, Mattheisen, M, Frank, J, Treutlein, J, Degenhardt, F, Breuer, R, Steffens, M, Mier, D, Esslinger, C, Walter, H, Kirsch, P, Erk, S, Schnell, K, Herms, S, Wichmann, HE, Schreiber, S, Jockel, KH, Strohmaier, J, Roeske, D, Haenisch, B, Gross, M, Hoefels, S, Lucae, S, Binder, EB, Wienker, TF, Schulze, TG, Schmal, C, Zimmer, A, Juraeva, D, Brors, B, Bettecken, T, Meyer-Lindenberg, A, Muller-Myhsok, B, Maier, W, Nothen, MM, Cichon, S (2010). Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression. Biological Psychiatry 68, 578585.
Schulze, TG, Hedeker, D, Zandi, P, Rietschel, M, McMahon, FJ (2006). What is familial about familial bipolar disorder? Resemblance among relatives across a broad spectrum of phenotypic characteristics. Archives of General Psychiatry 63, 13681376.
Shi, J, Potash, JB, Knowles, JA, Weissman, MM, Coryell, W, Scheftner, WA, Lawson, WB, DePaulo, JR Jr., Gejman, PV, Sanders, AR, Johnson, JK, Adams, P, Chaudhury, S, Jancic, D, Evgrafov, O, Zvinyatskovskiy, A, Ertman, N, Gladis, M, Neimanas, K, Goodell, M, Hale, N, Ney, N, Verma, R, Mirel, D, Holmans, P, Levinson, DF (2011). Genome-wide association study of recurrent early-onset major depressive disorder. Molecular Psychiatry 16, 193201.
Shyn, SI, Shi, J, Kraft, JB, Potash, JB, Knowles, JA, Weissman, MM, Garriock, HA, Yokoyama, JS, McGrath, PJ, Peters, EJ, Scheftner, WA, Coryell, W, Lawson, WB, Jancic, D, Gejman, PV, Sanders, AR, Holmans, P, Slager, SL, Levinson, DF, Hamilton, SP (2011). Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies. Molecular Psychiatry 16, 202215.
Solomon, DA, Keller, MB, Leon, AC, Mueller, TI, Lavori, PW, Shea, MT, Coryell, W, Warshaw, M, Turvey, C, Maser, JD, Endicott, J (2000). Multiple recurrences of major depressive disorder. American Journal of Psychiatry 157, 229233.
Solovieff, N, Cotsapas, C, Lee, PH, Purcell, SM, Smoller, JW (2013). Pleiotropy in complex traits: challenges and strategies. Nature Review Genetics 14, 483495.
StataCorp (2013). Stata Statistical Software: Release 13. StataCorp LP: College Station, TX.
Sullivan, PF, de Geus, EJ, Willemsen, G, James, MR, Smit, JH, Zandbelt, T, Arolt, V, Baune, BT, Blackwood, D, Cichon, S, Coventry, WL, Domschke, K, Farmer, A, Fava, M, Gordon, SD, He, Q, Heath, AC, Heutink, P, Holsboer, F, Hoogendijk, WJ, Hottenga, JJ, Hu, Y, Kohli, M, Lin, D, Lucae, S, Macintyre, DJ, Maier, W, McGhee, KA, McGuffin, P, Montgomery, GW, Muir, WJ, Nolen, WA, Nothen, MM, Perlis, RH, Pirlo, K, Posthuma, D, Rietschel, M, Rizzu, P, Schosser, A, Smit, AB, Smoller, JW, Tzeng, JY, van Dyck, R, Verhage, M, Zitman, FG, Martin, NG, Wray, NR, Boomsma, DI, Penninx, BW (2009). Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo. Molecular Psychiatry 14, 359375.
Sullivan, PF, Neale, MC, Kendler, KS (2000). Genetic epidemiology of major depression: review and meta-analysis. American Journal of Psychiatry 157, 15521562.
Tenesa, A, Haley, CS (2013). The heritability of human disease: estimation, uses and abuses. Nature Review Genetics 14, 139149.
Therneau, TM, Grambsch, PM (2000). Modeling Survival Data: Extending the Cox Model. Springer: New York.
Tozzi, F, Prokopenko, I, Perry, JD, Kennedy, JL, McCarthy, AD, Holsboer, F, Berrettini, W, Middleton, LT, Chilcoat, HD, Muglia, P (2008). Family history of depression is associated with younger age of onset in patients with recurrent depression. Psychological Medicine 38, 641649.
Uher, R, Maier, W, Hauser, J, Marusic, A, Schmael, C, Mors, O, Henigsberg, N, Souery, D, Placentino, A, Rietschel, M, Zobel, A, Dmitrzak-Weglarz, M, Petrovic, A, Jorgensen, L, Kalember, P, Giovannini, C, Barreto, M, Elkin, A, Landau, S, Farmer, A, Aitchison, KJ, McGuffin, P (2009). Differential efficacy of escitalopram and nortriptyline on dimensional measures of depression. British Journal of Psychiatry 194, 252259.
Visscher, PM, Hemani, G, Vinkhuyzen, AA, Chen, GB, Lee, SH, Wray, NR, Goddard, ME, Yang, J (2014). Statistical power to detect genetic (co)variance of complex traits using SNP data in unrelated samples. PLoS Genetics 10, e1004269.
Visscher, PM, Hill, WG, Wray, NR (2008). Heritability in the genomics era – concepts and misconceptions. Nature Review Genetics 9, 255266.
Visscher, PM, Yazdi, MH, Jackson, AD, Schalling, M, Lindblad, K, Yuan, QP, Porteous, D, Muir, WJ, Blackwood, DH (2001). Genetic survival analysis of age-at-onset of bipolar disorder: evidence for anticipation or cohort effect in families. Psychiatric Genetics 11, 129137.
Wing, JK, Babor, T, Brugha, T, Burke, J, Cooper, JE, Giel, R, Jablenski, A, Regier, D, Sartorius, N (1990). SCAN. Schedules for Clinical Assessment in Neuropsychiatry. Archives of General Psychiatry 47, 589593.
Wray, NR, Pergadia, ML, Blackwood, DH, Penninx, BW, Gordon, SD, Nyholt, DR, Ripke, S, MacIntyre, DJ, McGhee, KA, Maclean, AW, Smit, JH, Hottenga, JJ, Willemsen, G, Middeldorp, CM, de Geus, EJ, Lewis, CM, McGuffin, P, Hickie, IB, van den Oord, EJ, Liu, JZ, MacGregor, S, McEvoy, BP, Byrne, EM, Medland, SE, Statham, DJ, Henders, AK, Heath, AC, Montgomery, GW, Martin, NG, Boomsma, DI, Madden, PA, Sullivan, PF (2012). Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned. Molecular Psychiatry 17, 3648.
Wynants, L, Timmerman, D, Bourne, T, Van Huffel, S, Van Calster, B (2013). Screening for data clustering in multicenter studies: the residual intraclass correlation. BMC Medical Research Methodology 13, 128.
Yang, J, Lee, SH, Goddard, ME, Visscher, PM (2011). GCTA: a tool for genome-wide complex trait analysis. American Journal of Human Genetics 88, 7682.
Zaitlen, N, Kraft, P (2012). Heritability in the genome-wide association era. Human Genetics 131, 16551664.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary materials

Ferentinos supplementary material
Ferentinos supplementary material 1

 Unknown (94 KB)
94 KB


Altmetric attention score

Full text views

Total number of HTML views: 28
Total number of PDF views: 249 *
Loading metrics...

Abstract views

Total abstract views: 493 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 18th July 2018. This data will be updated every 24 hours.