Cognitive functioning and sex steroid hormone gene polymorphisms in women at midlife.

Single nucleotide polymorphism (SNP) genotype frequencies were examined to determine whether variation in 6 estrogen-related genes was associated with differences in cognitive functioning in women at midlife. DNA from a multiracial/multiethnic sample of 875 African American, Caucasian, Chinese, and Japanese women aged 45 to 56 years participating in the Study of Women's Health Across the Nation (SWAN) was genotyped. Gene markers from the sex steroid hormone pathway were linked to measures of cognitive functioning including the Digit Span Backward Test (DSB), a measure of working memory; the Symbol Digit Modalities Test (SDMT), a measure of perceptual speed; and the East Boston Memory Test (EBMT), a measure of episodic memory. Statistical models were fit using logistic regression and general linear models to estimate the strength of association of estrogen-related polymorphisms with DSB, SDMT, and EBMT scores. On the EBMT, African American women and Caucasian women with ESR1 rs9340799 GG genotypes had about 1.5 to 2.0 times greater odds of remembering story elements on the EBMT-immediate recall test. Caucasian women with ESR1 rs2234693 CC genotypes had 1.3 to 1.5 times greater odds of remembering story elements on the EBMT-delayed recall test. Chinese women with 17HSD rs615942 GG genotypes, 17HSD rs592389 TT genotypes, and 17HSD rs2830 GG genotypes had about 1.7 times greater odds of remembering story elements on the EBMT-immediate recall test. African American women with CYP 19 rs936306 CC genotypes had about 0.25 to 0.40 lower odds of remembering story elements on the EBMT-immediate recall test, whereas Chinese women with CYP 19 rs936306 CC genotypes had about 2.3 times greater odds of remembering story elements on both the EBMT-immediate and -delayed recall tests. On the DSB, African American women with CYP 19 rs749292 GG genotype had a higher mean score. On the SDMT, Japanese women with ESR1 rs728524 GG genotypes had a higher mean score. On the 3 tests of cognitive functioning, there was 1 significant finding for CYP1A1 and none for the CYP1B1 or ESR2 SNPs. We conclude that selected genes involved in estrogen synthesis and metabolism may be associated with performance differences on cognitive function tests. Also, the relevant estrogen-related polymorphisms may vary by race/ethnicity.