Identifying Ashkenazi Jewish BRCA1/2 founder variants in individuals who do not self-report Jewish ancestry.

Current guidelines recommend BRCA1 and BRCA2 genetic testing for individuals with a personal or family history of certain cancers. Three BRCA1/2 founder variants - 185delAG (c.68_69delAG), 5382insC (c.5266dupC), and 6174delT (c.5946delT) - are common in the Ashkenazi Jewish population. We characterized a cohort of more than 2,800 research participants in the 23andMe database who carry one or more of the three Ashkenazi Jewish founder variants, evaluating two characteristics that are typically used to recommend individuals for BRCA testing: self-reported Jewish ancestry and family history of breast, ovarian, prostate, or pancreatic cancer. Of the 1,967 carriers who provided self-reported ancestry information, 21% did not self-report Jewish ancestry; of these individuals, more than half (62%) do have detectable Ashkenazi Jewish genetic ancestry. In addition, of the 343 carriers who provided both ancestry and family history information, 44% did not have a first-degree family history of a BRCA-related cancer and, in the absence of a personal history of cancer, would therefore be unlikely to qualify for clinical genetic testing. These findings may help inform the discussion around broader access to BRCA genetic testing.

Validity of the cold pressor test and pain sensitivity questionnaire via online self-administration.

To determine the feasibility of complex home-based phenotyping, 1,876 research participants from the customer base of 23andMe completed an online version of a Pain Sensitivity Questionnaire (PSQ) as well as a cold pressor test (CPT) which is used in clinical assessments of pain. Overall our online version of the PSQ performed similarly to the original pen-and-paper version. Construct validity of the PSQ total was demonstrated by internal consistency and consistent discrimination between more and less painful items. Criterion validity was demonstrated by correlation with pain sensitivity as measured by the CPT. Within the same cohort we performed a cold pressor test using a layperson description and household equipment. Comparison with published reports from controlled studies revealed similar distributions of cold pain tolerance times (i.e., time elapsed before removing the hand from the water). Of those who elected to participate in the CPT, a large majority of participants did not report issues with the test procedure or noncompliance with the instructions (97%). We confirmed a large sex difference in CPT thresholds in line with published data, such that women removed their hands from the water at a median of 54.2 seconds, with men lasting for a median time of 82.7 seconds (Kruskal-Wallis statistic, p < 0.0001), but other factors like age or current pain treatment were at most weakly associated, and inconsistently between men and women. We introduce a new paradigm for performing pain testing, called testing@home, that, in the case of cold nociception, showed comparable results to studies conducted under controlled conditions and supervision of a health care professional.

Phenotypic analysis of 23andMe survey data: Treatment-resistant depression from participants' perspective.

To improve understanding of treatment-resistant depression (TRD) in a large population of individuals with depression, a self-reported antidepressant efficacy survey was designed and administered to 23andMe research participants. Participants with a current depressive episode or with a depressive episode within the last 5 years were queried for the effect of pharmacotherapy during the episode. TRD was defined as non-response to at least two antidepressants taken for at least 5-6 weeks. Non-TRD (NTRD) was defined as responsive to either the first or second medication taken for at least 3-4 weeks. Participants who could not be classified as TRD or NTRD were excluded from the analysis. Approximately 56,000 participants completed the survey, among which approximately 33,000 took medication for a depressive episode. The 3409 participants with self-reported TRD tended to have younger age of onset, and a more persistent course prior to initiation of treatment (e.g., a longer prior average episode duration and residual symptoms between episodes) than the 18,511 participants classified as NTRD. This survey identified depression characteristics, comorbidities, trigger events, and early childhood trauma that distinguish TRD from NTRD.

Adult stature, body proportions and age at menarche in the United States National Health and Nutrition Survey (NHANES) III.

BACKGROUND: Previous studies have found that age at menarche is associated with stature, primarily via leg length. However, the effects appear to vary by population and/or time period. Improving socioeconomic conditions might amplify the association. AIM: To test whether the association between early menarche and reduced stature in industrialized countries is mediated by leg length. To further test whether these effects are modified by years of education, as a proxy for socioeconomic conditions. SUBJECTS AND METHODS: The study used data on from 3174 21-40 year-old women who participated in the third National Health and Nutrition Survey of the US (NHANES III). The anthropometric measurements employed were stature, sitting height and upper leg length. Leg length, lower leg length and ratio of sitting height to leg length were calculated. RESULTS: Earlier menarche was associated with shorter stature, by ~ 3.9 mm per year of advancement, all of which was attributable to shorter leg length. Almost two-thirds of the effect was in the lower (distal) leg. Years of education did not significantly modify effects of pubertal timing on stature or body proportions. CONCLUSION: Socioeconomic conditions might not explain variable associations between linear body proportions and pubertal timing.

Age and size at maturity in women: a norm of reaction?

OBJECTIVES: We present the first review and meta-analysis of the association between adult stature and age at menarche over a broad range of human societies. We then outline possible biological explanations for observed empirical associations. METHODS: We analyzed the association between adult stature and age at menarche in 141 samples from published reports, including 35 samples for which the within-sample association was also reported. RESULTS: Overall and in small-scale societies, later age at menarche is associated with shorter adult stature. However, both between and within samples from industrialized societies, later age at menarche is associated with taller adult stature. CONCLUSIONS: The pattern of associations between adult stature and age at menarche may be explicable as a norm of reaction that evolved according to predictions of life history theory. However, nonadaptive explanations are also plausible, especially for the positive association observed in industrialized societies.

Sex differences in the fingers of 3 to 5month old infants do not predict concurrent salivary testosterone levels.

Testosterone was assayed in the saliva of 32 female and 42 male 3-5 month old infants, and the lengths of their finger segments between flexion creases were measured. While expected sex differences were identified in the finger measures, these sex differences were not correlated with salivary testosterone in either sex.

Female reproductive strategies in orangutans, evidence for female choice and counterstrategies to infanticide in a species with frequent sexual coercion.

Intersexual conflicts over mating can engender antagonistic coevolution of strategies, such as coercion by males and selective resistance by females. Orangutans are exceptional among mammals for their high levels of forced copulation. This has typically been viewed as an alternative mating tactic used by the competitively disadvantaged unflanged male morph, with little understanding of how female strategies may have shaped and responded to this behaviour. Here, we show that male morph is not by itself a good predictor of mating dynamics in wild Bornean orangutans but that female conception risk mediated the occurrence and quality of male-female interactions. Near ovulation, females mated cooperatively only with prime flanged males who they encountered at higher rates. When conception risk was low, willingness to associate and mate with non-prime males increased. Our results support the hypothesis that, together with concealed ovulation, facultative association is a mechanism of female choice in a species in which females can rarely avoid coercive mating attempts. Female resistance, which reduced copulation time, may provide an additional mechanism for mate selection. However, coercive factors were also important as prime males were frequently aggressive to females and females used mating strategies consistent with infanticide avoidance.

Bonobos have a more human-like second-to-fourth finger length ratio (2D:4D) than chimpanzees: a hypothesized indication of lower prenatal androgens.

The ratio of the second-to-fourth finger lengths (2D:4D) has been proposed as an indicator of prenatal sex differentiation. However, 2D:4D has not been studied in the closest living human relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). We report the results from 79 chimpanzees and 39 bonobos of both sexes, including infants, juveniles, and adults. We observed the expected sex difference in 2D:4D, and substantially higher, more human-like, 2D:4D in bonobos than chimpanzees. Previous research indicates that sex differences in 2D:4D result from differences in prenatal sex hormone levels. We hypothesize that the species difference in 2D:4D between bonobos and chimpanzees suggests a possible role for early exposure to sex hormones in the development of behavioral differences between the two species.

Weight change and ovarian steroid profiles in young women.

OBJECTIVE: To investigate possible short-term effects of voluntary weight loss on ovarian steroid profiles in young women, in light of better established long-term effects in older women. DESIGN: We tested for an association of voluntary weight change over the course of a menstrual cycle with salivary E(2) and P profiles in the same menstrual cycle. SETTING: Students were recruited in a college residence hall, and they provided daily saliva samples to a researcher living nearby. PATIENT(S): The 65 women who participated were all college students and ranged in age between 18 and 23 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Weight was assessed in the first week of the menstrual cycle and first week of the following menstrual cycle. Estradiol and P were measured by radioimmunoassay in daily saliva samples. RESULT(S): We did not detect a suppressive effect of weight loss on the overall level of either hormone. However, we did find evidence for more distinct follicular and luteal E(2) peaks in women who gained weight. Peak luteal P also arrived about 2 days earlier in women who gained weight. CONCLUSION(S): This finding adds to evidence that short-term response of ovarian function to weight loss in young women is less pronounced than long-term response in older women.

Prostate cancer risk and ESR1 TA, ESR2 CA repeat polymorphisms.

BACKGROUND: Experimental evidence has suggested that estrogen receptor alpha (coded by the gene ESR1) might increase prostate cancer risk, whereas estrogen receptor beta (coded by the gene ESR2) might reduce prostate cancer risk. METHODS: We investigated the relationship with prostate cancer risk of both a TA repeat polymorphism in the ESR1 5' region, ESR1 (TA)(n), and with a CA repeat polymorphism in intron 5 of ESR2, ESR2 (CA)(n), in a case-control study (545 cases and 674 controls) nested in the Physicians' Health Study. RESULTS: Prostate cancer risk was highest for carriers of ESR1 (TA)(24) and ESR1 (TA)(25). Replacing one modal ESR1 (TA)(14) allele with one ESR1 (TA)(24) allele yielded an odds ratio of 1.42 (95% confidence interval, 1.00-2.00; P=0.05). Replacing one ESR1 (TA)(14) allele with one ESR1 (TA)(25) allele yielded an odds ratio of 2.10 (95% confidence interval, 1.15-3.84; P=0.02). ESR2 (CA)(n) showed no effects on prostate cancer risk. CONCLUSIONS: The ESR1 (TA)(n) polymorphism might play a role in prostate cancer risk.

Index-to-ring finger length ratio (2D:4D) predicts levels of salivary estradiol, but not progesterone, over the menstrual cycle.

We tested the association between the index-to-ring finger length ratio (2D:4D) and ovarian steroid hormone concentrations measured over the course of a menstrual cycle in the saliva of 38 young women. Estradiol levels were positively associated with right-hand, but not left-hand, 2D:4D, and also with the difference between right- and left-hand 2D:4D. None of these measures predicted progesterone level.

Overconfidence in wargames: experimental evidence on expectations, aggression, gender and testosterone.

Overconfidence has long been noted by historians and political scientists as a major cause of war. However, the origins of such overconfidence, and sources of variation, remain poorly understood. Mounting empirical studies now show that mentally healthy people tend to exhibit psychological biases that encourage optimism, collectively known as 'positive illusions'. Positive illusions are thought to have been adaptive in our evolutionary past because they served to cope with adversity, harden resolve, or bluff opponents. Today, however, positive illusions may contribute to costly conflicts and wars. Testosterone has been proposed as a proximate mediator of positive illusions, given its role in promoting dominance and challenge behaviour, particularly in men. To date, no studies have attempted to link overconfidence, decisions about war, gender, and testosterone. Here we report that, in experimental wargames: (i) people are overconfident about their expectations of success; (ii) those who are more overconfident are more likely to attack; (iii) overconfidence and attacks are more pronounced among males than females; and (iv) testosterone is related to expectations of success, but not within gender, so its influence on overconfidence cannot be distinguished from any other gender specific factor. Overall, these results constitute the first empirical support of recent theoretical work linking overconfidence and war.

The use of digit ratios as markers for perinatal androgen action.

Since the ratio of the second-to-fourth finger length was first proposed as a marker for prenatal androgen action in 1998, over 100 studies have been published that have either further tested the association between the digit ratio and prenatal androgens, or employed digit ratios as a marker to investigate the association between prenatal androgens and a variety of outcomes, including behavior, fertility, and disease risks. Despite the clear demand for an adult marker of prenatal androgen action and increased use of digit ratios as such a marker, its validity remains controversial. This review (1) evaluates current evidence for the relationship between digit ratios and prenatal androgens (using experimentation with animal models, amniotic testosterone, and congenital adrenal hyperplasia case-control studies), (2) describes opportunities for future validation tests, and (3) compares the potential advantages and disadvantages of digit ratio measures with more established methods for studying the effects of prenatal androgens.

Sex dimorphism in digital formulae of children.

This paper presents results of a study designed to: 1) test for a sex difference in the relative lengths of the finger bones, including the second-to-fourth digit ratio (2D:4D), using left-hand radiographs taken in young children, 2) test whether sex differences can be explained by sex differences in fetal growth, and 3) test the serial stability of sex differences in relative digit lengths, including 2D:4D. Results are presented from 1,060 subjects of the California Child Health and Development Studies. One serial replication at about 9 years old is available from 271 subjects. Results indicate that relative digit lengths are sex-dimorphic in children (Manning et al. [1998] Hum. Reprod. 13:3000-3004, [2004] Early Hum. Dev. 80:161-168). Sex differences in digit length ratios are more pronounced within sibships, where shared family factors are controlled, and are not strongly associated with gross measures of fetal growth, like birth length or weight. Thus, sex differences in the fetal growth of the body are not implicated in sex differences in digital formulae, leaving open the possibility of more direct hormonal and/or genetic causation. However, 2D:4D declined between ages 6-8 in a longitudinal sample, and was a less consistent sex-dimorphic marker than 3D:4D across ethnic groups, suggesting that 3D:4D may be a better marker of perinatal sex differentiation. Prior conflicting findings about 2D:4D may be partly explained by variations in age and ethnicity of populations studied.

The development of sex differences in digital formula from infancy in the Fels Longitudinal Study.

Relative finger lengths, especially the second-to-fourth finger length ratio, have been proposed as useful markers for prenatal testosterone action. This claim partly depends on an association of relative finger lengths in adults with related sex differences in children and infants. This paper reports the results of a study using serial radiographs to test for both sex differences in the fingers of infants and children and for a relationship between sex differences in the children and infant finger and adult finger length ratios. This is the first study using long-term serial data to evaluate the validity of finger length ratios as markers. We found not only that sex differences in finger length ratios arise prior to puberty, but that sex differences in the fingers of children are highly correlated with adult finger length ratios. Our results strongly encourage the further use of finger length ratios as markers of perinatal testosterone action.

Human male pair bonding and testosterone.

Previous research in North America has supported the view that male involvement in committed, romantic relationships is associated with lower testosterone (T) levels. Here, we test the prediction that undergraduate men involved in committed, romantic relationships (paired) will have lower T levels than men not involved in such relationships (unpaired). Further, we also test whether these differences are more apparent in samples collected later, rather than earlier, in the day. For this study, 107 undergraduate men filled out a questionnaire and collected one saliva sample (from which a subject's T level was measured) at various times across the day. As in previous studies, men involved in committed, romantic relationships had lower salivary T levels, though only during later times of the day. Furthermore, additional analysis of the variation among unpaired subjects indicated that men without prior relationship experience had lower T levels than experienced men. Finally, while paired men as a group had lower T levels than unpaired men, those men at the earliest stage (less than six months) of a current relationship had higher T levels than unpaired men as well as men in longer-term relationships. These results suggest that variation in male testosterone levels may reflect differential behavioral allocation to mating effort.

Effects of developmental and adult androgens on male abdominal adiposity.

We present results from 42 gay men who completed a survey including self-measurement of waist circumference, height, and weight, in addition to providing saliva samples for the assay of testosterone, and a photocopy of the right hand for the measure of second-to-fourth digit length ratio (2D:4D), proposed as a means of approximating androgenic effects during development. The analyses were conducted as a test of the recent hypothesis, proposed by Abbott et al. ([2002] J Endocrinol 174:1-5), that high prenatal androgen exposure causes greater deposition of fat on the abdomen relative to other depots. We found support for this hypothesis in men, albeit in a limited sample and with self-reported and self-collected data.