Maternal age at the birth of the first child as an epistatic factor in polygenic disorders.

The identification of the genes for complex, polygenic disorders has proven difficult. This is due to the small effect size of each gene and genetic heterogeneity. An additional important factor could be the presence of unidentified epistatic factors. In the broad definition of epistasis, the effect of one unit is not predicable unless the value of another unit is known and one of the units may not be a gene. We have previously identified maternal age as an epistatic factor for the effect of the LEP gene on the age of onset of menarche. We report here the effect of maternal age and the age of the mother at the birth of her first child (maternal age 1st) as epistatic factors for the interaction of the dopamine D1 gene (DRD1) with obsessive-compulsive behaviors and with stuttering. The epistatic effects of maternal age 1st were stronger than maternal age. This type of epistatic factor may be generalizable to many other gene-trait interactions.

A multigene test for the risk of sporadic breast carcinoma.

BACKGROUND: Although the identification of the BRCA1 and BRCA2 genes have been of great interest, these genes account for less than 5% of all breast carcinoma cases. The remaining cases are sporadic. Reanalysis of a large twin study suggested that genetic factors may play a significant role in sporadic breast and other carcinomas. Sporadic breast carcinoma is polygenically inherited. Multiple genes are likely to have an additive effect, each gene accounting for a fraction of the variance. One factor that may have an impact on the development of hormonally responsive breast tumors is the duration of exposure of the breast to estrogen. Therefore, one of the demographic risk factors for breast carcinoma is an early age of onset of menarche. The current study was based on the hypothesis that genes that play a role in demographic risk factors may be breast carcinoma risk genes in their own right. The authors hypothesized that six genes relevant to the timing of the onset of menarche and related risk factors might be candidate genes for breast carcinoma. These were the leptin gene (LEP), the leptin receptor gene (LEPR), the catechol-0-methyltransferase gene (COMT), the dopamine D(2) receptor gene (DRD2), the estrogen 1 receptor gene (ESR1), and the androgen receptor gene (AR). METHODS: The authors examined 67 women with postmenopausal sporadic breast carcinoma and 145 gender and race-matched controls. RESULTS: Five of these genes accounted for a significant percent of the variance (r(2)) of breast carcinoma. The following r(2) and P values were calculated: LEP: 0.073, P < or = 0.0001; LEPR: 0.064, P < or = 0.0002; COMT: 0.073, P < or = 0.0001; AR: 0.040, P < or = 0.0035; and DRD2: 0.018, P < or = 0.05. When evaluated in a multivariate regression analysis, they accounted collectively for 24% of the variance of breast carcinoma (P < or = 0.0001). These genes accounted for 40% of the variance (P < or = 0.00001) in a subset of age-matched cases. Individual gene scores were added to form a breast carcinoma risk score (BCRS) that ranged from 0 to 17. When the BCRS was evaluated in a receiver operator characteristic plot, the area under the curve was 0.80 for the full set and 0.869 for the age-matched set. The relative breast carcinoma risk for the different BCRS scores ranged from 0.10 to 11.9. CONCLUSIONS: These results demonstrate a potentially powerful method of evaluating the additive effect of multiple breast carcinoma risk genes to form a potentially clinically useful assessment of women's risk for sporadic breast carcinoma.

Parent-daughter transmission of the androgen receptor gene as an explanation of the effect of father absence on age of menarche.

Based on an evolutionary theory of socialization, Belsky and colleagues proposed that girls exposed to a stressful environment, especially when due to father absence in the first 7 years of life, showed an early onset of puberty, precocious sexuality, and unstable relationships as adults. The authors of this article examined an alternative explanation that a variant X-linked androgen receptor (AR) gene, predisposing the father to behaviors that include family abandonment, may be passed to their daughters causing early puberty, precocious sexuality, and behavior problems. The results of a study of 121 White males and 164 White females showed a significant association of the short alleles of the GGC repeat polymorphism of the AR gene with a range of measures of aggression and impulsivity, increased number of sexual partners, sexual compulsivity, and lifetime number of sex partners in males; and paternal divorce, father absence, and early age of menarche in females. These findings support a genetic explanation of the Belsky psychosocial evolutionary hypothesis regarding the association of fathers' absence and parental stress with early age of onset of menarche and early sexual activity in their daughters. A genetic explanation of the father absence effect is proposed in which fathers carrying the AR alleles are more likely to abandon a marriage (father absence) and pass those alleles to their daughters in whom they produce an earlier age of menarche and behavioral problems.

Association of the muscarinic cholinergic 2 receptor (CHRM2) gene with major depression in women.

Cholinergic neurons have been implicated in depression and in the disorders of REM sleep in depression. We examined a common A-> T 1890 polymorphism in the 3' UTR of the cholinergic muscarinic receptor 2 (CHRM2) gene. There was a significant increase in the frequency of 11 homozygotes in 126 women with major depression (43.7%) compared to 304 women without major depression (25.7%), P =.001. There was no increase in the frequency of 11 homozygotes in 52 men with depression (26.9%) compared to 278 men without depression (27.7%). Regression analysis, scoring subjects with the 11 genotype as 1, and those with other genotypes as 0, showed that in women r(2) =.030, F = 13.37, P =.0003. By contrast, in men r(2) =.00001, F = 0.002, P =.96. These results are consistent with a gender-specific role of the CHRM2 gene in depression in women.

Association between the phenylethanolamine N-methyltransferase gene and multiple sclerosis.

Phenylethanolamine N-methyltransferase (PNMT), the terminal enzyme of the catecholamine biosynthesis pathway, catalyzes the conversion of norepinephrine (NE) to epinephrine (EPI). PNMT is a candidate gene for multiple sclerosis (MS) for two reasons. PNMT is known to map to a region identified in two genome screens for MS and it directly regulates the amounts of NE and EPI, both of which play a significant role in the modulation of the innate immune response. The frequencies of two promoter polymorphisms of the PNMT gene showed genetic association in a case-control study of 108 patients with MS and 774 ethnically and age-matched control subjects. In subjects with MS, significant differences in the frequency of the GG genotype at the G-387A marker and the AA genotype at the G-182A marker were observed. Additionally, when both markers were combined and evaluated, highly significant differences between the polymorphism distributions in patients with MS and control subjects were detected. The data suggest that these promoter polymorphisms of the PNMT gene, both independently and cumulatively, show association with MS.