Risk for premenstrual dysphoric disorder is associated with genetic variation in ESR1, the estrogen receptor alpha gene.
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.
Huo
Liang
L
Behavioral Endocrinology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
Straub
Richard E
RE
Roca
Catherine
C
Schmidt
Peter J
PJ
Shi
Kai
K
Vakkalanka
Radhakrishna
R
Weinberger
Daniel R
DR
Rubinow
David R
DR
D000328:Adult; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D016009:Chi-Square Distribution; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008183:Luteal Phase / Q000235:genetics / Q000523:psychology; D008875:Middle Aged; D019964:Mood Disorders / Q000150:complications / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011293:Premenstrual Syndrome / Q000150:complications / Q000235:genetics*
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D002394:Catechol O-Methyltransferase