Distribution of the FMR1 gene in females by race-ethnicity: women with diminished ovarian reserve versus women with normal fertility (SWAN study)

Abstract

ObjectivePremutation level trinucleotide repeat lengths in the FMR1 gene (CGG 55-199) are associated with primary ovarian insufficiency before age 40. However, an association between the repeat length with other ovarian aging phenotypes is not established. We examined whether reported associations between the FMR1 CGG repeat lengths in the intermediate, high normal, or low normal range differentiate women diagnosed with diminished ovarian reserve (DOR) from those with normal reproductive histories, and whether associations vary by race-ethnic group.DesignDOR cases (n=129) enrolled from 5 US fertility clinics vs. normal fertility female controls (n=803) from the US-based Study of Women's Health Across the Nation (SWAN).Materials and MethodsCases’ (95 Caucasians, 22 Asian, 12 other) and controls’ (386 Caucasians, 219 African-Americans, 102 Japanese, 96 Chinese) banked DNA was analyzed for FMR1 CGG repeat lengths. Cases were clinically diagnosed with DOR, with regular menses and no fragile X syndrome family history. Controls had >=1 menstrual period in the 3 months pre-enrollment, >=1 pregnancy, no history of infertility or hormonal therapy, and menopause ≥46 years. In a previous analysis the SWAN Chinese and Japanese groups had similar FMR1 CGG repeat lengths, so those two groups were combined. We used Fisher's exact tests to analyze data.ResultsWe found fewer CGG trinucleotide repeats in the lower of the two FMR1 alleles (i.e., allele with fewer repeats) in DOR cases relative to controls among Caucasians (p&lt0.0001), but not Asians (p=0.24). Caucasian DOR cases were more likely to have fewer CGG repeats in the lower allele compared with Asian DOR cases (p=0.027). No significant differences were found in the CGG repeat length distribution of the higher FMR1 allele among DOR cases compared with controls (p&gt0.20), or by race/ethnic group (p=0.41).ConclusionsThis study did not find an association between DOR and high normal/intermediate repeats, but there was an association between DOR and low normal repeats (<20 CGG) in Caucasians. Our study design is distinguished by its analysis of FMR1 CGG repeats by race-ethnic group and its large comparison group of women with normal fertility and normal menopausal histories. Variation in the expected distribution of CGG repeat lengths by race/ethnicity should be considered when determining whether distributions in patient populations are truly abnormal. A clear association between the trinucleotide repeat length and ovarian phenotypes, or lack thereof, will need to be demonstrated to allow patients, clinicians, and genetic counselors to correctly interpret FMR1 test results and make informed reproductive decisions. ObjectivePremutation level trinucleotide repeat lengths in the FMR1 gene (CGG 55-199) are associated with primary ovarian insufficiency before age 40. However, an association between the repeat length with other ovarian aging phenotypes is not established. We examined whether reported associations between the FMR1 CGG repeat lengths in the intermediate, high normal, or low normal range differentiate women diagnosed with diminished ovarian reserve (DOR) from those with normal reproductive histories, and whether associations vary by race-ethnic group. Premutation level trinucleotide repeat lengths in the FMR1 gene (CGG 55-199) are associated with primary ovarian insufficiency before age 40. However, an association between the repeat length with other ovarian aging phenotypes is not established. We examined whether reported associations between the FMR1 CGG repeat lengths in the intermediate, high normal, or low normal range differentiate women diagnosed with diminished ovarian reserve (DOR) from those with normal reproductive histories, and whether associations vary by race-ethnic group. DesignDOR cases (n=129) enrolled from 5 US fertility clinics vs. normal fertility female controls (n=803) from the US-based Study of Women's Health Across the Nation (SWAN). DOR cases (n=129) enrolled from 5 US fertility clinics vs. normal fertility female controls (n=803) from the US-based Study of Women's Health Across the Nation (SWAN). Materials and MethodsCases’ (95 Caucasians, 22 Asian, 12 other) and controls’ (386 Caucasians, 219 African-Americans, 102 Japanese, 96 Chinese) banked DNA was analyzed for FMR1 CGG repeat lengths. Cases were clinically diagnosed with DOR, with regular menses and no fragile X syndrome family history. Controls had >=1 menstrual period in the 3 months pre-enrollment, >=1 pregnancy, no history of infertility or hormonal therapy, and menopause ≥46 years. In a previous analysis the SWAN Chinese and Japanese groups had similar FMR1 CGG repeat lengths, so those two groups were combined. We used Fisher's exact tests to analyze data. Cases’ (95 Caucasians, 22 Asian, 12 other) and controls’ (386 Caucasians, 219 African-Americans, 102 Japanese, 96 Chinese) banked DNA was analyzed for FMR1 CGG repeat lengths. Cases were clinically diagnosed with DOR, with regular menses and no fragile X syndrome family history. Controls had >=1 menstrual period in the 3 months pre-enrollment, >=1 pregnancy, no history of infertility or hormonal therapy, and menopause ≥46 years. In a previous analysis the SWAN Chinese and Japanese groups had similar FMR1 CGG repeat lengths, so those two groups were combined. We used Fisher's exact tests to analyze data. ResultsWe found fewer CGG trinucleotide repeats in the lower of the two FMR1 alleles (i.e., allele with fewer repeats) in DOR cases relative to controls among Caucasians (p&lt0.0001), but not Asians (p=0.24). Caucasian DOR cases were more likely to have fewer CGG repeats in the lower allele compared with Asian DOR cases (p=0.027). No significant differences were found in the CGG repeat length distribution of the higher FMR1 allele among DOR cases compared with controls (p&gt0.20), or by race/ethnic group (p=0.41). We found fewer CGG trinucleotide repeats in the lower of the two FMR1 alleles (i.e., allele with fewer repeats) in DOR cases relative to controls among Caucasians (p&lt0.0001), but not Asians (p=0.24). Caucasian DOR cases were more likely to have fewer CGG repeats in the lower allele compared with Asian DOR cases (p=0.027). No significant differences were found in the CGG repeat length distribution of the higher FMR1 allele among DOR cases compared with controls (p&gt0.20), or by race/ethnic group (p=0.41). ConclusionsThis study did not find an association between DOR and high normal/intermediate repeats, but there was an association between DOR and low normal repeats (<20 CGG) in Caucasians. Our study design is distinguished by its analysis of FMR1 CGG repeats by race-ethnic group and its large comparison group of women with normal fertility and normal menopausal histories. Variation in the expected distribution of CGG repeat lengths by race/ethnicity should be considered when determining whether distributions in patient populations are truly abnormal. A clear association between the trinucleotide repeat length and ovarian phenotypes, or lack thereof, will need to be demonstrated to allow patients, clinicians, and genetic counselors to correctly interpret FMR1 test results and make informed reproductive decisions. This study did not find an association between DOR and high normal/intermediate repeats, but there was an association between DOR and low normal repeats (<20 CGG) in Caucasians. Our study design is distinguished by its analysis of FMR1 CGG repeats by race-ethnic group and its large comparison group of women with normal fertility and normal menopausal histories. Variation in the expected distribution of CGG repeat lengths by race/ethnicity should be considered when determining whether distributions in patient populations are truly abnormal. A clear association between the trinucleotide repeat length and ovarian phenotypes, or lack thereof, will need to be demonstrated to allow patients, clinicians, and genetic counselors to correctly interpret FMR1 test results and make informed reproductive decisions.