Skip to main content Accessibility help

Do genetic risk scores for body mass index predict risk of phobic anxiety? Evidence for a shared genetic risk factor

  • S. Walter (a1) (a2), M. M. Glymour (a1) (a2), K. Koenen (a3), L. Liang (a4) (a5), E. J. Tchetgen Tchetgen (a4) (a5), M. Cornelis (a6), S.-C. Chang (a1), M. Rewak (a1), E. Rimm (a4) (a6), I. Kawachi (a1) and L. D. Kubzansky (a1)...



Obesity and anxiety are often linked but the direction of effects is not clear.


Using genetic instrumental variable (IV) analyses in 5911 female participants from the Nurses' Health Study (NHS, initiated 1976) and 3697 male participants from the Health Professional Follow-up Study (HPFS, initiated 1986), we aimed to determine whether obesity increases symptoms of phobic anxiety. As instrumental variables we used the fat mass and obesity-associated (FTO) gene, the melanocortin 4 receptor (MC4R) gene and a genetic risk score (GRS) based on 32 single nucleotide polymorphisms (SNPs) that significantly predict body mass index (BMI). ‘Functional’ GRSs corresponding with specific biological pathways that shape BMI (adipogenesis, appetite and cardiopulmonary) were considered. The main outcome was phobic anxiety measured by the Crown Crisp Index (CCI) in 2004 in the NHS and in 2000 in the HPFS.


In observational analysis, a 1-unit higher BMI was associated with higher phobic anxiety symptoms [women: β = 0.05, 95% confidence interval (CI) 0.030–0.068; men: β = 0.04, 95% CI 0.016–0.071). IV analyses showed that BMI was associated with higher phobic anxiety symptoms in the FTO-instrumented analysis (p = 0.005) but not in the GRS-instrumented analysis (p = 0.256). Functional GRSs showed heterogeneous, non-significant effects of BMI on phobic anxiety symptoms.


Our findings do not provide conclusive evidence in favor of the hypothesis that higher BMI leads to higher levels of phobic anxiety, but rather suggest that genes that influence obesity, in particular FTO, may have direct effects on phobic anxiety, and hence that obesity and phobic anxiety may share common genetic determinants.


Corresponding author

* Address for correspondence: S. Walter, Ph.D., Department of Social and Behavioral Sciences, Harvard School of Public Health, Landmark Center, 445-C, 401 Park Drive, Boston, MA 02215, USA. (Email:


Hide All
Albert, CM, Chae, CU, Rexrode, KM, Manson, JAE, Kawachi, I (2005). Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women. Circulation 111, 480487.
Angrist, JD, Krueger, AB (1994). Split Sample Instrumental Variables. Technical Working Paper No. 150. National Bureau of Economic Research: Cambridge, MA.
Angrist, JD, Krueger, AB (1995). Split-sample instrumental variables estimates of the return to schooling. Journal of Business and Economic Statistics 13, 225235.
Bjerkeset, O, Romundstad, P, Evans, J, Gunnell, D (2008). Association of adult body mass index and height with anxiety, depression, and suicide in the general population: the HUNT study. American Journal of Epidemiology 167, 193202.
Bodenlos, JS, Lemon, SC, Schneider, KL, August, MA, Pagoto, SL (2011). Associations of mood and anxiety disorders with obesity: comparisons by ethnicity. Journal of Psychosomatic Research 71, 319324.
Bowden, J, Vansteelandt, S (2011). Mendelian randomization analysis of case-control data using structural mean models. Statistics in Medicine 30, 678694.
Cairney, J, Corna, LM, Veldhuizen, S, Kurdyak, P, Streiner, DL (2008). The social epidemiology of affective and anxiety disorders in later life in Canada. Canadian Journal of Psychiatry 53, 104111.
Chu, NF, Stampfer, MJ, Spiegelman, D, Rifai, N, Hotamisligil, GS, Rimm, EB (2001). Dietary and lifestyle factors in relation to plasma leptin concentrations among normal weight and overweight men. International Journal of Obesity 25, 106114.
Colditz, GA, Hankinson, SE (2005). The Nurses’ Health Study: lifestyle and health among women. Nature Reviews Cancer 5, 388396.
Crisp, A, Jones, MG, Slater, P (1978). The Middlesex Hospital Questionnaire: a validity study. British Journal of Medical Psychology 51, 269280.
Crown, S, Crisp, AH (1966). A short clinical diagnostic self-rating scale for psychoneurotic patients. The Middlesex Hospital Questionnaire (M.H.Q.). British Journal of Psychiatry 112, 917923.
Domschke, K, Reif, A (2012). Behavioral genetics of affective and anxiety disorders. Current Topics in Behavioral Neurosciences 12, 463502.
Gariepy, G, Nitka, D, Schmitz, N (2010). The association between obesity and anxiety disorders in the population: a systematic review and meta-analysis. International Journal of Obesity 34, 407419.
Glymour, MM, Tchetgen Tchetgen, EJ, Robins, JM (2012). Credible Mendelian randomization studies: approaches for evaluating the instrumental variable assumptions. American Journal of Epidemiology 175, 332339.
Haines, AP, Imeson, JD, Meade, TW (1987). Phobic anxiety and ischaemic heart disease. British Medical Journal (Clinical Research Edition) 295, 297299.
Hettema, JM, Neale, MC, Kendler, KS (2001). A review and meta-analysis of the genetic epidemiology of anxiety disorders. American Journal of Psychiatry 158, 15681578.
Hettema, JM, Prescott, CA, Myers, JM, Neale, MC, Kendler, KS (2005). The structure of genetic and environmental risk factors for anxiety disorders in men and women. Archives of General Psychiatry 62, 182189.
Irvine, J, Firestone, J, Ong, L, Cribbie, R, Dorian, P, Harris, L, Ritvo, P, Katz, J, Newman, D, Cameron, D (2011). A randomized controlled trial of cognitive behavior therapy tailored to psychological adaptation to an implantable cardioverter defibrillator. Psychosomatic Medicine 73, 226233.
Jokela, M, Elovainio, M, Keltikangas-Järvinen, L, David Batty, G, Hintsanen, M, Seppälä, I, Kähönen, M, Viikari, JS, Raitakari, OT, Lehtimäki, T (2012). Body mass index and depressive symptoms: instrumental-variables regression with genetic risk score. Genes, Brain and Behavior. Published online: 7 September 2012 . doi:10.1111/j.1601-183X.2012.00846.x.
Kawachi, I, Colditz, GA, Ascherio, A, Rimm, EB, Giovannucci, E, Stampfer, MJ, Willett, WC (1994). Prospective study of phobic anxiety and risk of coronary heart disease in men. Circulation 89, 19921997.
Kessler, RC, Aguilar-Gaxiola, S, Alonso, J, Chatterji, S, Lee, S, Ormel, J, Ustun, TB, Wang, PS (2009). The global burden of mental disorders: an update from the WHO World Mental Health (WMH) surveys. Epidemiologia e psichiatria sociale 18, 2333.
Kessler, RC, Berglund, P, Demler, O, Jin, R, Merikangas, KR, Walters, EE (2005). Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 62, 593602.
Kessler, RC, Petukhova, M, Sampson, NA, Zaslavsky, AM, Wittchen, HU (2012). Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. International Journal of Methods in Psychiatric Research 21, 169184.
Kivimaki, M, Jokela, M, Hamer, M, Geddes, J, Ebmeier, K, Kumari, M, Singh-Manoux, A, Hingorani, A, Batty, GD (2011). Examining overweight and obesity as risk factors for common mental disorders using fat mass and obesity-associated (FTO) genotype-instrumented analysis: the Whitehall II Study, 1985–2004. American Journal of Epidemiology 173, 421429.
Lawlor, DA, Harbord, RM, Tybjaerg Hansen, A, Palmer, TM, Zacho, J, Benn, M, Timpson, NJ, Davey Smith, G, Nordestgaard, BG (2011). Using genetic loci to understand the relationship between adiposity and psychological distress: a Mendelian Randomization study in the Copenhagen General Population Study of 53,221 adults. Journal of Internal Medicine 269, 525537.
Leis, JA, Heron, J, Stuart, EA, Mendelson, T (2014). Associations between maternal mental health and child emotional and behavioral problems: does prenatal mental health matter? Journal of Abnormal Child Psychology 42, 161171.
Mavissakalian, M, Michelson, L (1981). The Middlesex Hospital Questionnaire: a validity study with American psychiatric patients. Britisch Journal of Psychiatry 139, 336340.
Nousen, EK, Franco, JG, Sullivan, EL (2013). Unraveling the mechanisms responsible for the comorbidity between metabolic syndrome and mental health disorders. Neuroendocrinology 98, 254266.
Oldroyd, JC, Cyril, S, Wijayatilaka, BS, O'Neil, A, McKenzie, DP, Zavarsek, S, Sanderson, K, Hare, DL, Fisher, AJ, Forbes, AB, Barr Taylor, C, Clarke, DM, Meredith, IT, Oldenburg, B (2013). Evaluating the impact of depression, anxiety & autonomic function on health related quality of life, vocational functioning and health care utilisation in acute coronary syndrome patients: the ADVENT study protocol. BMC Cardiovascular Disorders 13, 103.
Price, AL, Patterson, NJ, Plenge, RM, Weinblatt, ME, Shadick, NA, Reich, D (2006). Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics 38, 904909.
Purcell, SM, Wray, NR, Stone, JL, Visscher, PM, O'Donovan, MC, Sullivan, PF, Sklar, P, Ruderfer, DM, McQuillin, A, Morris, DW (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748752.
Rimm, EB, Stampfer, MJ, Colditz, GA, Chute, CG, Litin, LB, Willett, WC (1990). Validity of self-reported waist and hip circumferences in men and women. Epidemiology 1, 466–73.
Samaan, Z, Anand, SS, Zhang, X, Desai, D, Rivera, M, Pare, G, Thabane, L, Xie, C, Gerstein, H, Engert, JC, Craig, I, Cohen-Woods, S, Mohan, V, Diaz, R, Wang, X, Liu, L, Corre, T, Preisig, M, Kutalik, Z, Bergmann, S, Vollenweider, P, Waeber, G, Yusuf, S, Meyre, D (2013). The protective effect of the obesity-associated rs9939609 A variant in fat mass- and obesity-associated gene on depression. Molecular Psychiatry 18, 12811286.
Sareen, J, Cox, BJ, Clara, I, Asmundson, GJ (2005). The relationship between anxiety disorders and physical disorders in the US National Comorbidity Survey. Depression and Anxiety 21, 193202.
Smoller, JW (2011). Who's afraid of anxiety genetics? Biological Psychiatry 69, 506507.
Smoller, JW, Gardner-Schuster, E, Covino, J (2008). The genetic basis of panic and phobic anxiety disorders. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 148C, 118126.
Speliotes, EK, Willer, CJ, Berndt, SI, Monda, KL, Thorleifsson, G, Jackson, AU, Allen, HL, Lindgren, CM, Luan, J, Mägi, R (2010). Association analyses of 2 49 796 individuals reveal 18 new loci associated with body mass index. Nature Genetics 42, 937948.
Tchetgen Tchetgen, EJ, Walter, S, Glymour, MM (2013). Commentary: building an evidence base for mendelian randomization studies: assessing the validity and strength of proposed genetic instrumental variables. International Journal of Epidemiology 42, 328331.
VanderWeele, TJ (2012). Invited commentary: structural equation models and epidemiologic analysis. American Journal of Epidemiology 176, 608612.
Young, JPR, Fenton, GW, Lader, MH (1971). The inheritance of neurotic traits: a twin study of the Middlesex Hospital Questionnaire. British Journal of Psychiatry 119, 393398.


Related content

Powered by UNSILO
Type Description Title
Supplementary materials

Walter Supplementary Material
Supplementary Information

 Word (160 KB)
160 KB

Do genetic risk scores for body mass index predict risk of phobic anxiety? Evidence for a shared genetic risk factor

  • S. Walter (a1) (a2), M. M. Glymour (a1) (a2), K. Koenen (a3), L. Liang (a4) (a5), E. J. Tchetgen Tchetgen (a4) (a5), M. Cornelis (a6), S.-C. Chang (a1), M. Rewak (a1), E. Rimm (a4) (a6), I. Kawachi (a1) and L. D. Kubzansky (a1)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.