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Genetic analysis of activity, brain and behavioral associations in extended families with heavy genetic loading for bipolar disorder

  • Annabel Vreeker (a1) (a2), Scott C. Fears (a2), Susan K. Service (a2), Lucia Pagani (a3) (a4), Joseph S. Takahashi (a3) (a5), Carmen Araya (a6), Xinia Araya (a6), Julio Bejarano (a6), Maria C. Lopez (a7), Gabriel Montoya (a7), Claudia Patricia Montoya (a7), Terri M. Teshiba (a2), Javier Escobar (a8), Rita M. Cantor (a2), Carlos López-Jaramillo (a7) (a9), Gabriel Macaya (a6), Julio Molina (a10), Victor I. Reus (a11), Chiara Sabatti (a12), Roel A. Ophoff (a2) (a13), Nelson B. Freimer (a2) (a13) and Carrie E. Bearden (a2) (a13) (a14)...



Disturbed sleep and activity are prominent features of bipolar disorder type I (BP-I). However, the relationship of sleep and activity characteristics to brain structure and behavior in euthymic BP-I patients and their non-BP-I relatives is unknown. Additionally, underlying genetic relationships between these traits have not been investigated.


Relationships between sleep and activity phenotypes, assessed using actigraphy, with structural neuroimaging (brain) and cognitive and temperament (behavior) phenotypes were investigated in 558 euthymic individuals from multi-generational pedigrees including at least one member with BP-I. Genetic correlations between actigraphy-brain and actigraphy-behavior associations were assessed, and bivariate linkage analysis was conducted for trait pairs with evidence of shared genetic influences.


More physical activity and longer awake time were significantly associated with increased brain volumes and cortical thickness, better performance on neurocognitive measures of long-term memory and executive function, and less extreme scores on measures of temperament (impulsivity, cyclothymia). These associations did not differ between BP-I patients and their non-BP-I relatives. For nine activity-brain or activity-behavior pairs there was evidence for shared genetic influence (genetic correlations); of these pairs, a suggestive bivariate quantitative trait locus on chromosome 7 for wake duration and verbal working memory was identified.


Our findings indicate that increased physical activity and more adequate sleep are associated with increased brain size, better cognitive function and more stable temperament in BP-I patients and their non-BP-I relatives. Additionally, we found evidence for pleiotropy of several actigraphy-behavior and actigraphy-brain phenotypes, suggesting a shared genetic basis for these traits.


Corresponding author

Author for correspondence: Carrie E. Bearden, E-mail:


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Aas, M., Djurovic, S., Ueland, T., Mørch, R. H., Fjæra Laskemoen, J., Reponen, E. J., … Andreassen, O. A. (2019). The relationship between physical activity, clinical and cognitive characteristics and BDNF mRNA levels in patients with severe mental disorders. The World Journal of Biological Psychiatry, 20, 567576.
Abramovic, L., Boks, M. P., Vreeker, A., Bouter, D. C., Kruiper, C., Verkooijen, S., … van Haren, N. E. (2016). The association of antipsychotic medication and lithium with brain measures in patients with bipolar disorder. European Neuropsychopharmacology, 26, 17411751.
Abramovitch, A., Goldzweig, G., & Schweiger, A. (2013). Correlates of physical activity with intrusive thoughts, worry and impulsivity in adults with attention deficit/hyperactivity disorder: a cross-sectional pilot study. The Israel Journal of Psychiatry and Related Sciences, 50, 4754.
Acebo, C., & LeBourgeois, M. K. (2006). Actigraphy. Respiratory Care Clinics of North America, 12, 2330, viii.
Akiskal, H. S., & Akiskal, K. K. (2005). TEMPS: Temperament Evaluation of Memphis, Pisa, Paris and San Diego. Journal of Affective Disorders, 85, 12.
Alhola, P., & Polo-Kantola, P. (2007). Sleep deprivation: impact on cognitive performance. Neuropsychiatric Disease and Treatment, 3, 553.
Almasy, L., & Blangero, J. (1998). Multipoint quantitative-trait linkage analysis in general pedigrees. The American Journal of Human Genetics, 62, 11981211.
American Psychiatric Association, A. P. A., Force, D.S.M.T. (2013). Diagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association.
Anderson, C., & Platten, C. R. (2011). Sleep deprivation lowers inhibition and enhances impulsivity to negative stimuli. Behavioural Brain Research, 217, 463466.
Barrett, J. C., Fry, B., Maller, J., & Daly, M. J. (2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics (Oxford, England), 21, 263265.
Barron, F., & Welsh, G. S. (1952). Artistic perception as a possible factor in personality style: its measurement by a figure preference test. The Journal of Psychology, 33, 199203.
Bearden, C. E., Hoffman, K. M., & Cannon, T. D. (2001). The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. Bipolar Disorders, 3, 106150.
Beebe, L. H., Tian, L., Morris, N., Goodwin, A., Allen, S. S., & Kuldau, J. (2005). Effects of exercise on mental and physical health parameters of persons with schizophrenia. Issues in Mental Health Nursing, 26, 661676.
Bherer, L., Erickson, K. I., & Liu-Ambrose, T. (2013). A review of the effects of physical activity and exercise on cognitive and brain functions in older adults. Journal of Aging Research, 2013, 657508.
Bugg, J. M., & Head, D. (2011). Exercise moderates age-related atrophy of the medial temporal lobe. Neurobiology of Aging, 32, 506514.
Buss, A. H., & Perry, M. (1992). The aggression questionnaire. Journal of Personality and Social Psychology, 63, 452459.
Carvajal-Carmona, L. G., Ophoff, R., Service, S., Hartiala, J., Molina, J., Leon, P., … Ruiz-Linares, A. (2003). Genetic demography of Antioquia (Colombia) and the Central Valley of Costa Rica. Human Genetics, 112, 534541.
Cretu, J. B., Culver, J. L., Goffin, K. C., Shah, S., & Ketter, T. A. (2016). Sleep, residual mood symptoms, and time to relapse in recovered patients with bipolar disorder. Journal of Affective Disorders, 190, 162166.
De Crescenzo, F., Economou, A., Sharpley, A. L., Gormez, A., & Quested, D. J. (2017). Actigraphic features of bipolar disorder: a systematic review and meta-analysis. Sleep Medicine Reviews, 33, 5869.
Diekelmann, S., & Born, J. (2010). The memory function of sleep. Nature Reviews Neuroscience, 11, 114.
Durmer, J. S., & Dinges, D. F. (2005). Neurocognitive consequences of sleep deprivation. In Roos, K. L. & Avidan, A. Y. (Eds.), Seminars in neurology (pp. 117129). New York, NY 10001, USA: Thieme Medical Publishers, Inc. Copyright© 2005.
Erickson, K. I., Hillman, C. H., & Kramer, A. F. (2015). Physical activity, brain, and cognition. Current Opinion in Behavioral Sciences, 4, 2732.
Erickson, K. I., Leckie, R. L., & Weinstein, A. M. (2014). Physical activity, fitness, and gray matter volume. Neurobiology of Aging, 35, S20S28.
Fears, S. C., Schür, R., Sjouwerman, R., Service, S. K., Araya, C., Araya, X., … Bearden, C. E. (2015). Brain structure–function associations in multi-generational families genetically enriched for bipolar disorder. Brain, 138, 20872102.
Fears, S. C., Service, S. K., Kremeyer, B., Araya, C., Araya, X., Bejarano, J., … Bearden, C. E. (2014). Multisystem component phenotypes of bipolar disorder for genetic investigations of extended pedigrees. JAMA Psychiatry, 71, 375387.
Freimer, N. B., Reus, V. I., Escamilla, M., Spesny, M., Smith, L., Service, S., … Sandkuijl, L. A. (1996). An approach to investigating linkage for bipolar disorder using large Costa Rican pedigrees. American Journal of Medical Genetics, 67, 254263.
Glahn, D. C., Almasy, L., Barguil, M., Hare, E., Peralta, J. M., Kent, J. W. Jr., … Escamilla, M. A. (2010). Neurocognitive endophenotypes for bipolar disorder identified in multiplex multigenerational families. Archives of General Psychiatry, 67, 168177.
Hamilton, M. (1960). A rating scale for depression. Journal of Neurology Neurosurgery & Psychiatry, 23, 5662.
He, J. P., Paksarian, D., & Merikangas, K. R. (2018). Physical activity and mental disorder among adolescents in the United States. The Journal of Adolescent Health, 63, 628635.
Heath, S. C. (1997). Markov chain Monte Carlo segregation and linkage analysis for oligogenic models. American Journal of Human Genetics, 61, 748760.
Heath, S. C., Snow, G. L., Thompson, E. A., Tseng, C., & Wijsman, E. M. (1997). MCMC segregation and linkage analysis. Genetic Epidemiology, 14, 10111016.
Herzberg, I., Jasinska, A., Garcia, J., Jawaheer, D., Service, S., Kremeyer, B., … Ruiz-Linares, A. (2006). Convergent linkage evidence from two Latin-American population isolates supports the presence of a susceptibility locus for bipolar disorder in 5q31-34. Human Molecular Genetics, 15, 31463153.
Hibar, D., Westlye, L. T., van Erp, T. G., Rasmussen, J., Leonardo, C. D., Faskowitz, J., … Agartz, I. (2016). Subcortical volumetric abnormalities in bipolar disorder. Molecular Psychiatry, 21, 17101716.
Hibar, D. P., Westlye, L. T., Doan, N. T., Jahanshad, N., Cheung, J. W., Ching, C. R. K., … Andreassen, O. A. (2018). Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. Molecular Psychiatry, 23, 932942.
Hong, K. S., McInnes, L. A., Service, S. K., Song, T., Lucas, J., Silva, S., … Freimer, N. B. (2004). Genetic mapping using haplotype and model-free linkage analysis supports previous evidence for a locus predisposing to severe bipolar disorder at 5q31-33. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 125b, 8386.
Jackson, A., Cavanagh, J., & Scott, J. (2003). A systematic review of manic and depressive prodromes. Journal of Affective Disorders, 74, 209217.
Kamphuis, J., Meerlo, P., Koolhaas, J. M., & Lancel, M. (2012). Poor sleep as a potential causal factor in aggression and violence. Sleep Medicine, 13, 327334.
Kanady, J. C., Soehner, A. M., Klein, A. B., & Harvey, A. G. (2017). The association between insomnia-related sleep disruptions and cognitive dysfunction during the inter-episode phase of bipolar disorder. Journal of Psychiatric Research, 88, 8088.
Kronholm, E., Sallinen, M., Suutama, T., Sulkava, R., Era, P., & Partonen, T. (2009). Self-reported sleep duration and cognitive functioning in the general population. Journal of Sleep Research, 18, 436446.
Kyle, S. D., Sexton, C. E., Feige, B., Luik, A., Lane, J., Saxena, R. & Spiegelhalder, K. (2017). Sleep and cognitive performance: cross-sectional associations from the UK Biobank. Sleep Medicine, 38, 8591.
Lane, J. M., Liang, J., Vlasac, I., Anderson, S. G., Bechtold, D. A., Bowden, J. & Saxena, R. (2017). Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits. Nature Genetics, 49, 274281.
Lunsford-Avery, J. R., Orr, J. M., Gupta, T., Pelletier-Baldelli, A., Dean, D. J., Smith Watts, A. K. & Mittal, V. A. (2013). Sleep dysfunction and thalamic abnormalities in adolescents at ultra high-risk for psychosis. Schizophrenia Research, 151, 148153.
Merikangas, K. R., Swendsen, J., Hickie, I. B., Cui, L., Shou, H., Merikangas, A. K. & Zipunnikov, V. (2018). Real-time mobile monitoring of the dynamic associations among motor activity, energy, mood, and sleep in adults with bipolar disorder. JAMA Psychiatry, 76(2), 190198.
Milhiet, V., Etain, B., Boudebesse, C., & Bellivier, F. (2011). Circadian biomarkers, circadian genes and bipolar disorders. Journal of Physiology-Paris, 105, 183189.
Najt, P., Perez, J., Sanches, M., Peluso, M. A. M., Glahn, D., & Soares, J. C. (2007). Impulsivity and bipolar disorder. European Neuropsychopharmacology, 17, 313320.
Nurnberger, J. I. Jr., Blehar, M. C., Kaufmann, C. A., York-Cooler, C., Simpson, S. G., Harkavy-Friedman, J., … Reich, T. (1994). Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH genetics initiative. Archives of General Psychiatry, 51, 849859; discussion 863–4.
Pagani, L. St. Clair, P. A., Teshiba, T. M., Service, S. K., Fears, S. C., Araya, C., … Freimer, N. B. (2016). Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder. Proceedings of the National Academy of Sciences, 113, E754E761.
Palacio, C. A., Garcia, J., Arbelaez, M. P., Sanchez, R., Aguirre, B., Garces, I. C., … Ospina, J. (2004). Validation of the Diagnostic Interview for Genetic Studies (DIGS) in Colombia. Biomedica: Revista del Instituto Nacional de Salud, 24, 5662.
Paluska, S. A., & Schwenk, T. L. (2000). Physical activity and mental health. Sports Medicine, 29, 167180.
Patton, J. H., Stanford, M. S., & Barratt, E. S. (1995). Factor structure of the Barratt impulsiveness scale. Journal of Clinical Psychology, 51, 768774.
Peters, E., Joseph, S., Day, S., Garety, P. (2004). Measuring delusional ideation: the 21-item Peters et al. Delusions Inventory (PDI). Schizophrenia Bulletin, 30, 10051022.
Rimol, L. M., Hartberg, C. B., Nesvag, R., Fennema-Notestine, C., Hagler, D. J. Jr., Pung, C. J., … Agartz, I. (2010). Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder. Biological Psychiatry, 68, 4150.
Russo, M., Mahon, K., Shanahan, M., Ramjas, E., Solon, C., Purcell, S. M. & Burdick, K. E. (2015). The relationship between sleep quality and neurocognition in bipolar disorder. Journal of Affective Disorders, 187, 156162.
Service, S., DeYoung, J., Karayiorgou, M., Roos, J. L., Pretorious, H., Bedoya, G., … Freimer, N. (2006). Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies. Nature Genetics, 38, 556560.
Sexton, C. E., Storsve, A. B., Walhovd, K. B., Johansen-Berg, H., & Fjell, A. M. (2014). Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults. Neurology, 83, 967973.
Sheehan, D. V., Lecrubier, Y., Sheehan, K. H., Amorim, P., Janavs, J., Weiller, E., … Dunbar, G. C. (1998). The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry, 59(Suppl. 20), 2233; quiz 34–57.
Spira, A. P., Gonzalez, C. E., Venkatraman, V. K., Wu, M. N., Pacheco, J., Simonsick, E. M., … Resnick, S. M. (2016). Sleep duration and subsequent cortical thinning in cognitively normal older adults. Sleep, 39, 11211128.
Srivastava, S., Childers, M. E., Baek, J. H., Strong, C. M., Hill, S. J., Warsett, K. S., … Ketter, T. A. (2010). Toward interaction of affective and cognitive contributors to creativity in bipolar disorders: a controlled study. Journal of Affective Disorders, 125, 2734.
Stephens, T. (1988). Physical activity and mental health in the United States and Canada: evidence from four population surveys. Preventive Medicine, 17, 3547.
Stoffers, D., Moens, S., Benjamins, J., van Tol, M.-J., Penninx, B. W. J. H., Veltman, D. J., … Van Someren, E. J. W. (2012). Orbitofrontal gray matter relates to early morning awakening: a neural correlate of insomnia complaints? Frontiers in Neurology, 3, 105.
Van der Waerden, B. L. (1952). Order tests for the two-sample problem and their power. Indagationes Mathematicae, 14, 458.
Verkooijen, S., Stevelink, R., Abramovic, L., Vinkers, C. H., Ophoff, R. A., Kahn, R. S., … van Haren, N. E. (2017). The association of sleep and physical activity with integrity of white matter microstructure in bipolar disorder patients and healthy controls. Psychiatry Research, 262, 7180.
Volkert, J., Kopf, J., Kazmaier, J., Glaser, F., Zierhut, K. C., Schiele, M. A., … Reif, A. (2015). Evidence for cognitive subgroups in bipolar disorder and the influence of subclinical depression and sleep disturbances. European Neuropsychopharmacology, 25, 192202.
Vreeker, A., Boks, M., Abramovic, L., Verkooijen, S., Van Bergen, A., Hillegers, M., … GROUP investigators. (2016). High educational performance is a distinctive feature of bipolar disorder: a study on cognition in bipolar disorder, schizophrenia patients, relatives and controls. Psychological Medicine, 46, 807818.
Weinstein, A. M., Voss, M. W., Prakash, R. S., Chaddock, L., Szabo, A., White, S. M., … Erickson, K. I. (2012). The association between aerobic fitness and executive function is mediated by prefrontal cortex volume. Brain, Behavior, and Immunity, 26, 811819.
Xu, L., Jiang, C. Q., Lam, T. H., Liu, B., Jin, Y. L., Zhu, T., … Thomas, G. N. (2011). Short or long sleep duration is associated with memory impairment in older Chinese: the Guangzhou Biobank Cohort Study. Sleep, 34, 575580.
Young, R. C., Biggs, J. T., Ziegler, V. E., & Meyer, D. A. (1978). A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry, 133, 429435.
Zhou, X., & Stephens, M. (2014). Efficient multivariate linear mixed model algorithms for genome-wide association studies. Nature Methods, 11, 407409.


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Genetic analysis of activity, brain and behavioral associations in extended families with heavy genetic loading for bipolar disorder

  • Annabel Vreeker (a1) (a2), Scott C. Fears (a2), Susan K. Service (a2), Lucia Pagani (a3) (a4), Joseph S. Takahashi (a3) (a5), Carmen Araya (a6), Xinia Araya (a6), Julio Bejarano (a6), Maria C. Lopez (a7), Gabriel Montoya (a7), Claudia Patricia Montoya (a7), Terri M. Teshiba (a2), Javier Escobar (a8), Rita M. Cantor (a2), Carlos López-Jaramillo (a7) (a9), Gabriel Macaya (a6), Julio Molina (a10), Victor I. Reus (a11), Chiara Sabatti (a12), Roel A. Ophoff (a2) (a13), Nelson B. Freimer (a2) (a13) and Carrie E. Bearden (a2) (a13) (a14)...


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