Risk for Premenstrual Dysphoric Disorder Is Associated with Genetic Variation in ESR1, the Estrogen Receptor Alpha Gene

• Published in: Biological psychiatry (1969) Vol. 62; no. 8; pp. 925 - 933
• Main Authors: Huo, Liang, Straub, Richard E, Roca, Catherine, Schmidt, Peter J, Shi, Kai, Vakkalanka, Radhakrishna, Weinberger, Daniel R, Rubinow, David R
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15-10-2007; Elsevier Science
• Subjects: Adult; Biological and medical sciences; Catechol O-Methyltransferase - genetics; Chi-Square Distribution; ESR1; Estrogen Receptor alpha - genetics; estrogen receptor alpha gene; Estrogen Receptor beta - genetics; Female; Female genital diseases; Gene Frequency; Genetic Predisposition to Disease; Gynecology. Andrology. Obstetrics; Haplotypes; Humans; Linkage Disequilibrium; Luteal Phase - genetics; Luteal Phase - psychology; Medical sciences; Middle Aged; Mood Disorders - complications; Mood Disorders - genetics; Non tumoral diseases; PMDD; Polymorphism, Single Nucleotide; premenstrual dysphoric disorder; Premenstrual Syndrome - complications; Premenstrual Syndrome - genetics; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; PMDD; estrogen receptor alpha gene; premenstrual dysphoric disorder; ESR1; Estrogen receptor; Menstruation disorders; Genetic variability; Genetic determinism; Female genital diseases; Gene; Risk factor; Genetics; Premenstrual syndrome
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2006.12.019

Background Premenstrual dysphoric disorder (PMDD) is a heritable mood disorder that is triggered by gonadal steroids during the luteal phase in susceptible women. Methods We performed haplotype analyses of estrogen receptors alpha and beta (ESR1 and ESR2) in 91 women with prospectively confirmed PMDD and 56 control subjects to investigate possible sources of the genetic susceptibility to affective dysregulation induced by normal levels of gonadal steroids. We also examined associations with the valine (Val)158methionine (Met) single nucleotide polymorphism (SNP) of the gene for catechol-O-methyltransferase (COMT), an enzyme involved in estrogen metabolism and prefrontal cortical activation. Results Four SNPs in intron 4 of ESR1 showed significantly different genotype and allele distributions between patients and control subjects. Significant case-control differences were seen in sliding-window analyses of two-, three-, and four-marker haplotypes but only in those haplotypes containing SNPs in intron 4 that were positive in the single-locus analysis. No significant associations were observed with ESR2 or with the COMT Val158Met polymorphism, although the significant associations with ESR1 were observed only in those with the Val/Val genotype. Conclusions These are the first positive (albeit preliminary) genetic findings in this reproductive endocrine-related mood disorder and involve the receptor for a hormone that is pathogenically relevant.