David E. Comings

A dopamine D3 receptor genotype is associated with hyperandrogenic chronic anovulation and resistant to ovulation induction with clomiphene citrate in female Hispanics.

OBJECTIVEnTo determine if dopamine (D3) receptor genotypes are associated with anovulation and response to ovulation induction with clomiphene citrate.nnnDESIGNnClinical and laboratory characteristics of anovulatory patients and ovulatory controls were compared with findings at the DNA level.nnnSETTINGnAn outpatient clinic at an university medical center.nnnPATIENTSnOne hundred eighty human Hispanic female volunteers (130 of these with documented ovulatory status) were studied.nnnINTERVENTIONSnGenomic DNAs were extracted from each patient. Polymerase chain reaction with subsequent restriction digest was performed to analyze the D3 receptor allele status (two possible alleles).nnnMAIN OUTCOME MEASURESnMenstrual history, serum T, and midluteal serum Ps from spontaneous and clomiphene cycles were correlated with D3 receptor genotype.nnnRESULTSnHispanic females with the 22 genotype compared with the other genotypes (11 and 12) were more likely to have irregular menses, an elevated serum T (> or = 70 ng/dL [conversion factor to SI unit, 3.467]), and hyperandrogenic chronic anovulation. These patients tended to be resistant to ovulation induction requiring a significantly higher dose of clomiphene to achieve an ovulatory response (22 genotype [mean +/- SEM] [140.0 +/- 19.0 mg] versus 11 [77.1 +/- 17.5 mg] or 12 [69.2 +/- 13.1 mg]). This effect was independent of patient age, weight, or serum T level.nnnCONCLUSIONSnHyperandrogenic chronic anovulation may have a genetic component. Genetic analysis may be useful in predicting resistance to ovulation induction with clomiphene.

Genetic Influences on Childbearing Motivation: Further Testing a Theoretical Framework

In a previous paper (Miller et al., 1999), we developed and tested a theoretical framework linking human childbearing motivation to a neural substrate in the central nervous system. Central to this motivational model was a four-step psychological sequence that we postulated to underlie reproductive decision-making. The sequence begins with motivational traits, which lead to desires, then to intentions, and finally result in instrumental reproductive behaviors. Here, we re-examine and expand upon our framework, generating a new synthesis suitable for testing with genetic and psychological data.

Evidence of an Emerging Collision Between the Fertility Transition and Genotype-Dependent Fertility Differentials

In most industri alize nations, and in many developing countries as well, infant and child mortality rates have dropped precipitously while fertility is under increasingly active constraint, generating the so-called “fertility transition.” Within such a context, those genetic alleles that have been maintained in populations to compens ate for variation in disease vulnerability, and those alleles having relevance to sexual behavior, can be expected to experience increas ing selection pressure. Several examples of genotype-dependent fertility differenti als have been reported, prompting the present study. We examined the association between alleles at the dopamine D2 receptor gene (DRD2) TaqI site in a sample of 293 adult males from Catacamas, Honduras. Carriers of the A1 allele were found to have an earlier age at birth of their first child (p=.024) and increased total fertility (p=.007) relative to A1subjects. These data suggest that the 30% decline in fertility observed in Honduras during the past 25 years may be due to a disproportionate constraint on reproductive activity on the part of A1- males. Moreover, these findings also suggest that we should be able to expect that the DRD2 TaqI A1 allele will increase in prevalence in Honduras. These results, and those of other investigators, raise the possibility that changes in allelic frequencies, as an unexpected consequence of the fertility transition, may be playing a role in the observed increases in the prevalence of many so-called “diseases of modernization.”

Studies of human germinal mutations by deoxyribonucleic acid hybridization.

Spontaneous mutations that occur in human germ cells contribute significantly to clinical disorders and result in premature mortality, incurable morbidity, mental handicap, and infertility. We have used molecular analysis of deoxyribonucleic acid to study the occurrence of spontaneous human germinal mutations. We examined 458 offspring and parents in 60 multigeneration human families. Probes for hypervariable loci were dispersed throughout all chromosomes to note the occurrence of new mutations. We found that both point mutations and insertion-deletion mutations occur frequently enough to be directly quantitated. The rates of occurrence detected at the molecular level are much greater than the rates detected with other modalities. The mutational rates at some loci approach 1% in live-born children. Such mutations appear to be sequence specific and related to the processes of meiosis or mitosis as they occur in the production of human gametes.

Associations Between the Endothelial Nitric Oxide Synthase Gene (NOS3), Reproductive Behaviors, and Twinning

Fertility decline in industrialized nations, fuelled by increased educational opportunity and delayed marriage/childbearing, is a driving force in reshaping contemporary population structure. These same forces have contributed to an increase in twinning, due to fertility drugs, but a possible decline in natural dizygotic twinning. Twinning has been linked to elevations in testosterone and age-related increases in follicle-stimulating hormone. Using data from 473 females, we examined the role of the regulatory gene for nitric oxide synthase (NOS3) in fertility-related events and in the vulnerability to preeclampsia, or pregnancy-induced hypertension (PIH). We found that the 2-allele of a biallelic marker for this gene was associated with increased risk of PIH, with testosterone, with LH/FSH ratio, and with earlier age at menarche. Subsequent studies of the mothers of twins revealed that the NOS3 2-allele was associated with earlier maternal age at the birth of the twins, less education, and increased monozygotic twinning rate among females with birth ages <30. Additionally, 2-allele carriers evaluated by the multiphasic personality questionnaire had elevated scores for aggression and decreased scores for achievement orientation. These data suggest that, other events equal, the NOS3 2-allele carriers would outproduce NOS3 1-allele carriers, eventually threatening the viability of the 1-allele. However, prior to recent advances in medicine, preeclampsia, linked to the 2-allele, is thought to have had a roughly 40% rate of maternal/fetal mortality, balancing the selective advantages otherwise conferred upon the 2-allele.