Joeri J Meijsen1,2, Hanyang Shen1, Mytilee Vemuri1, Natalie L Rasgon1, Karestan C Koenen3, Laramie E Duncan1. 1. Department of Psychiatry and Behavioral Sciences, Stanford University, 401 Quarry Road, Stanford, CA94305, USA. 2. Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Boserupvej 2, 4000Roskilde, Denmark. 3. Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA, USA.
Abstract
BACKGROUND: Women experience major depression and post-traumatic stress disorder (PTSD) approximately twice as often as men. Estrogen is thought to contribute to sex differences in these disorders, and reduced estrogen is also known to be a key driver of menopause symptoms such as hot flashes. Moreover, estrogen is used to treat menopause symptoms. In order to test for potential shared genetic influences between menopause symptoms and psychiatric disorders, we conducted a genome-wide association study (GWAS) of estrogen medication use (as a proxy for menopause symptoms) in the UK Biobank. METHODS: The analysis included 232 993 women aged 39-71 in the UK Biobank. The outcome variable for genetic analyses was estrogen medication use, excluding women using hormonal contraceptives. Trans-ancestry GWAS meta-analyses were conducted along with genetic correlation analyses on the European ancestry GWAS results. Hormone usage was also tested for association with depression and PTSD. RESULTS: GWAS of estrogen medication use (compared to non-use) identified a locus in the TACR3 gene, which was previously linked to hot flashes in menopause [top rs77322567, odds ratio (OR) = 0.78, p = 7.7 × 10-15]. Genetic correlation analyses revealed shared genetic influences on menopause symptoms and depression (rg = 0.231, s.e.= 0.055, p = 2.8 × 10-5). Non-genetic analyses revealed higher psychiatric symptoms scores among women using estrogen medications. CONCLUSIONS: These results suggest that menopause symptoms have a complex genetic etiology which is partially shared with genetic influences on depression. Moreover, the TACR3 gene identified here has direct clinical relevance; antagonists for the neurokinin 3 receptor (coded for by TACR3) are effective treatments for hot flashes.
BACKGROUND: Women experience major depression and post-traumatic stress disorder (PTSD) approximately twice as often as men. Estrogen is thought to contribute to sex differences in these disorders, and reduced estrogen is also known to be a key driver of menopause symptoms such as hot flashes. Moreover, estrogen is used to treat menopause symptoms. In order to test for potential shared genetic influences between menopause symptoms and psychiatric disorders, we conducted a genome-wide association study (GWAS) of estrogen medication use (as a proxy for menopause symptoms) in the UK Biobank. METHODS: The analysis included 232 993 women aged 39-71 in the UK Biobank. The outcome variable for genetic analyses was estrogen medication use, excluding women using hormonal contraceptives. Trans-ancestry GWAS meta-analyses were conducted along with genetic correlation analyses on the European ancestry GWAS results. Hormone usage was also tested for association with depression and PTSD. RESULTS: GWAS of estrogen medication use (compared to non-use) identified a locus in the TACR3 gene, which was previously linked to hot flashes in menopause [top rs77322567, odds ratio (OR) = 0.78, p = 7.7 × 10-15]. Genetic correlation analyses revealed shared genetic influences on menopause symptoms and depression (rg = 0.231, s.e.= 0.055, p = 2.8 × 10-5). Non-genetic analyses revealed higher psychiatric symptoms scores among women using estrogen medications. CONCLUSIONS: These results suggest that menopause symptoms have a complex genetic etiology which is partially shared with genetic influences on depression. Moreover, the TACR3 gene identified here has direct clinical relevance; antagonists for the neurokinin 3 receptor (coded for by TACR3) are effective treatments for hot flashes.
Authors: Megan R Gerber; Matthew W King; Suzanne L Pineles; Shannon Wiltsey-Stirman; Bevanne Bean-Mayberry; Sandra J Japuntich; Sally G Haskell Journal: J Gen Intern Med Date: 2014-11-06 Impact factor: 5.128
Authors: Naomi E Rance; Penny A Dacks; Melinda A Mittelman-Smith; Andrej A Romanovsky; Sally J Krajewski-Hall Journal: Front Neuroendocrinol Date: 2013-07-17 Impact factor: 8.606
Authors: Hadine Joffe; Sybil L Crawford; Marlene P Freeman; David P White; Matt T Bianchi; Semmie Kim; Nicole Economou; Julie Camuso; Janet E Hall; Lee S Cohen Journal: J Clin Endocrinol Metab Date: 2016-09-28 Impact factor: 5.958
Authors: Rebecca B Lawn; Kristen M Nishimi; Yongjoo Kim; Sun Jae Jung; Andrea L Roberts; Jennifer A Sumner; Rebecca C Thurston; Lori B Chibnik; Eric B Rimm; Andrew D Ratanatharathorn; Shaili C Jha; Karestan C Koenen; Shelley S Tworoger; Laura D Kubzansky Journal: Cancer Epidemiol Biomarkers Prev Date: 2020-12-21 Impact factor: 4.254
Authors: Channa N Jayasena; Alexander N Comninos; Evgenia Stefanopoulou; Adam Buckley; Shakunthala Narayanaswamy; Chioma Izzi-Engbeaya; Ali Abbara; Risheka Ratnasabapathy; Julianne Mogford; Noel Ng; Zubair Sarang; Mohammad A Ghatei; Stephen R Bloom; Myra S Hunter; Waljit S Dhillo Journal: Sci Rep Date: 2015-02-16 Impact factor: 4.379
Authors: L E Duncan; A Ratanatharathorn; A E Aiello; L M Almli; A B Amstadter; A E Ashley-Koch; D G Baker; J C Beckham; L J Bierut; J Bisson; B Bradley; C-Y Chen; S Dalvie; L A Farrer; S Galea; M E Garrett; J E Gelernter; G Guffanti; M A Hauser; E O Johnson; R C Kessler; N A Kimbrel; A King; N Koen; H R Kranzler; M W Logue; A X Maihofer; A R Martin; M W Miller; R A Morey; N R Nugent; J P Rice; S Ripke; A L Roberts; N L Saccone; J W Smoller; D J Stein; M B Stein; J A Sumner; M Uddin; R J Ursano; D E Wildman; R Yehuda; H Zhao; M J Daly; I Liberzon; K J Ressler; C M Nievergelt; K C Koenen Journal: Mol Psychiatry Date: 2017-04-25 Impact factor: 15.992