Genome-wide association study identifies 48 common genetic variants associated with handedness.

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10-8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.

Definitive Zygosity Scores in the Peas in the Pod Questionnaire is a Sensitive and Accurate Assessment of the Zygosity of Adult Twins.

Twin researchers face the challenge of accurately determining the zygosity of twins for research. As part of the annual questionnaire between 1999 and 2006, 8,307 twins from the TwinsUK registry were asked to complete five questions (independently from their co-twin) to ascertain their self-perceived zygosity during childhood on up to five separate occasions. This questionnaire is known as the 'peas in the pod' questionnaire (PPQ), but there is little evidence of its validation. Answers were scored and classified as monozygotic (MZ), dizygotic (DZ), or unknown zygosity (UZ) and were compared with 4,484 twins with genotyping data who had not been selected for zygosity. Of these, 3,859 individuals (46.5% of those who had a zygosity from PPQ) had zygosity classified by both the PPQ and genotyping. Of the 708 individual twins whose answers meant that they were consistently classed as MZ in the PPQ, 683 (96.5%) were MZ within the genotype data. Of the 945 individual twins consistently classed as DZ within questionnaire, 936 (99.0%) were DZ in the genotype data. Where both twins scored MZ consistently across multiple questionnaires, 99.6% were MZ on genotyping, 99.7% were DZ on genotyping if both twins consistently scored DZ. However, for the initial questionnaire, 88.6% of those scoring as MZ were genotypically MZ and 98.7% DZ. For twin pairs where both scored UZ, 94.7% were DZ. Using the PPQ on a single occasion provided a definitive classification of whether the twin was MZ or DZ with an overall accuracy of 86.9%, increasing to 97.9% when there was a consistent classification of zygosity across multiple questionnaires. This study has shown that the PPQ questionnaire is an excellent proxy indicator of zygosity in the absence of genotyping information.

Evaluating the consent preferences of UK research volunteers for genetic and clinical studies.

OBJECTIVES: To establish the views of research volunteers on the consent process; to explore their views on the consent process in different research scenarios; to inform debate on emerging models of consent for participation in research. DESIGN, SETTING AND PARTICIPANTS: 2,308 adult volunteers from the TwinsUK Registry (www.twinsuk.ac.uk) completed an online survey about their views on the consent process for use of their DNA and medical information in research. Their views on the re-consenting process in different scenarios were assessed. RESULTS: The majority of volunteers preferred to be informed of the identity of the main researcher of a study in which they are participating, which is contrary to current practice. Over 80% were willing to complete the consent process online instead of face to face. On the whole, respondents did not view their DNA differently from their medical information with regard to the consent process. Research participants were more willing to give broad consent to cover future research if their DNA was to be used by the original researcher than by another researcher, even if the disease under investigation varied, in contrast to the traditional 'gold standard' whereby specific consent is required for all new research projects. DISCUSSION: In some scenarios, research participants reported that they would be comfortable with not signing a new consent form for future research uses of their data and DNA, and are comfortable with secure, online consent processes rather than traditional face-to-face consent processes. Our findings indicate that the perceived relationship between research participants and researchers plays an important role in shaping preferences regarding the consent process and suggest that this relationship is not captured by traditional consent processes. We argue that the development of new formats of consent should be informed by empirical research on volunteers' perceptions and preferences regarding the consent process.

Genome-wide association analysis of eating disorder-related symptoms, behaviors, and personality traits.

Eating disorders (EDs) are common, complex psychiatric disorders thought to be caused by both genetic and environmental factors. They share many symptoms, behaviors, and personality traits, which may have overlapping heritability. The aim of the present study is to perform a genome-wide association scan (GWAS) of six ED phenotypes comprising three symptom traits from the Eating Disorders Inventory 2 [Drive for Thinness (DT), Body Dissatisfaction (BD), and Bulimia], Weight Fluctuation symptom, Breakfast Skipping behavior and Childhood Obsessive-Compulsive Personality Disorder trait (CHIRP). Investigated traits were derived from standardized self-report questionnaires completed by the TwinsUK population-based cohort. We tested 283,744 directly typed SNPs across six phenotypes of interest in the TwinsUK discovery dataset and followed-up signals from various strata using a two-stage replication strategy in two independent cohorts of European ancestry. We meta-analyzed a total of 2,698 individuals for DT, 2,680 for BD, 2,789 (821 cases/1,968 controls) for Bulimia, 1,360 (633 cases/727 controls) for Childhood Obsessive-Compulsive Personality Disorder trait, 2,773 (761 cases/2,012 controls) for Breakfast Skipping, and 2,967 (798 cases/2,169 controls) for Weight Fluctuation symptom. In this GWAS analysis of six ED-related phenotypes, we detected association of eight genetic variants with P < 10(-5) . Genetic variants that showed suggestive evidence of association were previously associated with several psychiatric disorders and ED-related phenotypes. Our study indicates that larger-scale collaborative studies will be needed to achieve the necessary power to detect loci underlying ED-related traits.

A survey of UK public interest in internet-based personal genome testing.

BACKGROUND: In view of the increasing availability of commercial internet-based Personal Genome Testing (PGT), this study aimed to explore the reasons why people would consider taking such a test and how they would use the genetic risk information provided. METHODOLOGY/PRINCIPAL FINDINGS: A self-completion questionnaire assessing public awareness and interest in PGT and motivational reasons for undergoing PGT was completed by 4,050 unselected adult volunteers from the UK-based TwinsUK register, aged 17 to 91 (response rate 62%). Only 13% of respondents were aware of the existence of PGT. After reading a brief summary about PGT, one in twenty participants (5%) were potentially interested at current prices (£250), however this proportion rose to half (50%) if the test was free of charge. Nearly all respondents who were interested in free PGT reported they would take the test to encourage them to adopt a healthier lifestyle if found to be at high genetic risk of a disease (93%). Around 4 in 5 respondents would have the test to convey genetic risk information to their children and a similar proportion felt that having a PGT would enable their doctor to monitor their health more closely. A TwinsUK research focus group also indicated that consumers would consult their GP to help interpret results of PGT. CONCLUSIONS/SIGNIFICANCE: This hypothetical study suggests that increasing publicity and decreasing costs of PGT may lead to increased uptake, driven in part by the general public's desire to monitor and improve their health. Although the future extent of the clinical utility of PGT is currently unknown, it is crucial that consumers are well informed about the current limitations of PGT. Our results suggest that health professionals will inevitably be required to respond to individuals who have undergone PGT. This has implications for health service providers regarding both cost and time.

Phenotypic and genetic relations between the HEXACO dimensions and trait emotional intelligence.

The present study investigated the location of trait emotional intelligence (trait EI or trait emotional self-efficacy) within the context of the HEXACO model - a more comprehensive personality framework than the conventional Big Five structure. A total of 666 MZ and 526 DZ adult twin pairs from the United Kingdom completed the short form of the Trait Emotional Intelligence Questionnaire (TEIQue-SF) and the short form of the HEXACO Personality Inventory (HEXACO-60). Many significant phenotypic correlations between the TEIQue-SF and the HEXACO-60 were obtained, which were strongest for HEXACO Extraversion, and weakest for HEXACO Honesty-Humility. As was expected, Emotionality was the only HEXACO dimension to correlate negatively with TEIQue-SF scores. Bivariate behavioral genetic analyses revealed that all phenotypic correlations were attributable to common genetic and common nonshared environmental factors. The study confirms the validity of trait EI as a constellation of emotional self-perceptions located at the lower levels of personality.

A general factor of personality: evidence from the HEXACO model and a measure of trait emotional intelligence.

The purpose of the present study was to determine if a general factor of personality (GFP) could be extracted from the six dimensions of the HEXACO model and four factors of trait emotional intelligence. Participants were 1,192 pairs of twins (666 MZ pairs, 526 DZ pairs) between the ages of 19 to 86 years, who completed the Trait Emotional Intelligence Questionnaire - Short Form and the HEXACO Personality Inventory - Revised. Principal components analysis yielded a strong GFP accounting for 33% of the variance, on which all variables with the exception of honesty-humility from the HEXACO showed moderate to large loadings. Behavioral genetic (BG) analyses revealed that individual differences in the GFP were entirely attributable to additive genetic and non-shared environmental factors - results that are in accord with previous BG analyses of a GFP. The present study adds to the body of evidence in support of a heritable GFP but an alternative perspective is also discussed.

A genome-wide study of common SNPs and CNVs in cognitive performance in the CANTAB.

Psychiatric disorders such as schizophrenia are commonly accompanied by cognitive impairments that are treatment resistant and crucial to functional outcome. There has been great interest in studying cognitive measures as endophenotypes for psychiatric disorders, with the hope that their genetic basis will be clearer. To investigate this, we performed a genome-wide association study involving 11 cognitive phenotypes from the Cambridge Neuropsychological Test Automated Battery. We showed these measures to be heritable by comparing the correlation in 100 monozygotic and 100 dizygotic twin pairs. The full battery was tested in approximately 750 subjects, and for spatial and verbal recognition memory, we investigated a further 500 individuals to search for smaller genetic effects. We were unable to find any genome-wide significant associations with either SNPs or common copy number variants. Nor could we formally replicate any polymorphism that has been previously associated with cognition, although we found a weak signal of lower than expected P-values for variants in a set of 10 candidate genes. We additionally investigated SNPs in genomic loci that have been shown to harbor rare variants that associate with neuropsychiatric disorders, to see if they showed any suggestion of association when considered as a separate set. Only NRXN1 showed evidence of significant association with cognition. These results suggest that common genetic variation does not strongly influence cognition in healthy subjects and that cognitive measures do not represent a more tractable genetic trait than clinical endpoints such as schizophrenia. We discuss a possible role for rare variation in cognitive genomics.

No clear genetic influences on the association between dyslexia and anxiety in a population-based sample of female twins.

Individuals with dyslexia are at an increased risk for anxiety disorders (e.g. generalized anxiety disorder, stress disorders, panic disorder). The extent to which this association is mediated by genetic and/or environmental influences is unclear. The current study explored the relationship between these two phenotypes using a large population-based twin sample. In total, 940 monozygotic and 903 dizygotic female twin pairs were included in the analyses. The presence of dyslexia and anxiety was determined by self-report of diagnosis by a health professional. Tetrachoric correlations confirmed an association between the two phenotypes, but suggested that there was no evidence for shared genetic risks. Bivariate twin modelling corroborated this finding and indicated the relationship between dyslexia and anxiety is mediated by shared environmental factors. Future research should seek to identifying the environmental factors that increase the vulnerability of individuals with dyslexia to emotional problems should be a priority for future research.

The Three-Factor Eating Questionnaire, body mass index, and responses to sweet and salty fatty foods: a twin study of genetic and environmental associations.

BACKGROUND: The relation between body weight and energy-dense foods remains unclear. OBJECTIVE: We estimated the effects of genetic and environmental factors on cognitive and emotional aspects of dieting behavior, body mass index (BMI), and responses to fatty foods and on their relations. DESIGN: A total of 1326 adult twin persons (aged 17-82 y; 17% M and 83% F) from the United Kingdom and Finland completed the revised version of the Three-Factor Eating Questionnaire (TFEQ-R18) and reported the liking and use-frequency of 4 sweet-and-fatty and salty-and-fatty food items (6 items in the United Kingdom and 5 items in Finland). Genetic modeling was done by using linear structural equations. RESULTS: Heritability estimates were calculated separately for the countries and sexes; they were 26-63% for cognitive restraint, 45-69% for uncontrolled eating, and 9-45% for emotional eating, respectively. Of the variation in liking and use-frequency of fatty foods, 24-54% was attributed to interindividual genetic differences. No significant correlations were observed between BMI and fatty food use or liking. However, BMI was positively (mostly genetically) correlated (genetic r = 0.16-0.51) with all of the dieting behaviors, and they correlated with fatty food use and liking ratings. Uncontrolled eating was both genetically and environmentally associated with liking for salty-and-fatty foods (genetic and environmental r = 0.16), and emotional eating was genetically associated with liking for sweet-and-fatty foods (genetic r = 0.31). CONCLUSIONS: The relation between BMI and diet appears to be mediated through dieting behaviors. Dietary counseling should focus on unhealthy dieting behaviors rather than only on direct advice on food use.

Normal variations in personality are associated with coital orgasmic infrequency in heterosexual women: a population-based study.

INTRODUCTION: As many as 20-30% of women report an inability to orgasm during sexual intercourse. Some female sexual problems have been reported to cluster with psychological and social problems. Underlying personality type may play a role in the development or maintenance of such problems. AIM: The aim of this study was to investigate whether certain domains of personality are associated with female coital orgasmic infrequency. To our knowledge this is the first such study in a large unselected population. METHODS: A total of 2632 women (mean age 51) from the TwinsUK registry completed questionnaires relating to personality and sexual behavior. Personality domains were assessed using the validated Ten-Item Personality Index (TIPI). Coital orgasmic frequency was measured using a seven-point Likert scale. MAIN OUTCOME MEASURES: Using logistic regression, we investigated whether variations in five domains of personality are associated with female coital orgasmic infrequency. Discordant twin analysis was used to verify findings. RESULTS: Introversion (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.7-3.7), emotional instability (OR 2.0, 95% CI 1.3-3.1), and not being open to new experience (OR 2.4, 95% CI 1.6-3.6) were significantly associated with orgasmic infrequency, whereas indices of agreeableness and conscientiousness were not significantly associated with orgasm frequency. CONCLUSION: Specific personality subtypes appear to be significant risk factors for orgasmic infrequency. Consideration of these behavioral risk factors may need to be incorporated into research into female orgasmic disorder, and possible approaches to its treatment.

Genetic and environmental contributions to humor styles: a replication study.

One thousand and seventy three pairs of adult monozygotic (MZ) twins and 895 pairs of same sex adult dizygotic (DZ) twins from the United Kingdom (UK) completed the Humor Styles Questionnaire: a 32-item measure which assesses two positive and two negative styles of humor. MZ correlations were approximately twice as large as DZ correlations for all four humor styles, and univariate behavioral genetic model fitting indicated that individual differences in all of them can be accounted for entirely by genetic and nonshared environmental factors, with heritabilities ranging from .34 to .49. These results, while perhaps not surprising, are somewhat at odds with a previous study that we conducted in North America (Vernon et al., in press) in which genetic factors contributed significantly to individual differences in the two positive humor styles, but contributed far less to the two negative styles, variance in which was instead largely due to shared and nonshared environmental factors. We suggest that differences between North American and UK citizens in their appreciation of different kinds of humor may be responsible for the different results obtained in these two studies.

Offspring's leukocyte telomere length, paternal age, and telomere elongation in sperm.

Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offspring's LTLs in 4 different cohorts. Moreover, we examined the potential cause of the paternal age on offspring's LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18-94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young (<30 years) and older (>50 years) donors. Paternal age had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age. Moreover, sperm telomere length analyses were compatible with the emergence in older men of a subset of sperm with elongated telomeres. Paternal age exerts a considerable effect on the offspring's LTL, a phenomenon which might relate to telomere elongation in sperm from older men. The implications of this effect deserve detailed study.

The association between physical activity in leisure time and leukocyte telomere length.

BACKGROUND: Physical inactivity is an important risk factor for many aging-related diseases. Leukocyte telomere dynamics (telomere length and age-dependent attrition rate) are ostensibly a biological indicator of human aging. We therefore tested the hypothesis that physical activity level in leisure time (over the past 12 months) is associated with leukocyte telomere length (LTL) in normal healthy volunteers. METHODS: We studied 2401 white twin volunteers, comprising 2152 women and 249 men, with questionnaires on physical activity level, smoking status, and socioeconomic status. Leukocyte telomere length was derived from the mean terminal restriction fragment length and adjusted for age and other potential confounders. RESULTS: Leukocyte telomere length was positively associated with increasing physical activity level in leisure time (P< .001); this association remained significant after adjustment for age, sex, body mass index, smoking, socioeconomic status, and physical activity at work. The LTLs of the most active subjects were 200 nucleotides longer than those of the least active subjects (7.1 and 6.9 kilobases, respectively; P= .006). This finding was confirmed in a small group of twin pairs discordant for physical activity level (on average, the LTL of more active twins was 88 nucleotides longer than that of less active twins; P= .03). CONCLUSIONS: A sedentary lifestyle (in addition to smoking, high body mass index, and low socioeconomic status) has an effect on LTL and may accelerate the aging process. This provides a powerful message that could be used by clinicians to promote the potentially antiaging effect of regular exercise.

Same genetic components underlie different measures of sweet taste preference.

BACKGROUND: Sweet taste preferences are measured by several often correlated measures. OBJECTIVE: We examined the relative proportions of genetic and environmental effects on sweet taste preference indicators and their mutual correlations. DESIGN: A total of 663 female twins (324 complete pairs, 149 monozygous and 175 dizygous pairs) aged 17-80 y rated the liking and intensity of a 20% (wt/vol) sucrose solution, reported the liking and the use-frequency of 6 sweet foods (sweet desserts, sweets, sweet pastry, ice cream, hard candy, and chocolate), and completed a questionnaire on cravings of sweet foods. The estimated contributions of genetic factors, environmental factors shared by a twin pair, and environmental factors unique to each twin individual to the variance and covariance of the traits were obtained with the use of linear structural equation modeling. RESULTS: Approximately half of the variation in liking for sweet solution and liking and use-frequency of sweet foods (49-53%) was explained by genetic factors, whereas the rest of the variation was due to environmental factors unique to each twin individual. Sweet taste preference-related traits were correlated. Tetravariate modeling showed that the correlation between liking for the sweet solution and liking for sweet foods was due to genetic factors (genetic r = 0.27). Correlations between liking, use-frequency, and craving for sweet foods were due to both genetic and unshared environmental factors. CONCLUSION: Detailed information on the associations between preference measures is an important intermediate goal in the determination of the genetic components affecting sweet taste preferences.

Dietary patterns and heritability of food choice in a UK female twin cohort.

To examine the contribution of genetic factors to food choice, we determined dietary patterns from food frequency questionnaires in 3262 UK female twins aged 18 to 79 years. Five distinct dietary patterns were identified (fruit and vegetable, high alcohol, traditional English, dieting, low meat) that accounted for 22% of the total variance. These patterns are similar to those found in other singleton Western populations, and were related to body mass index, smoking status, physical activity and deprivation scores. Older subjects had higher scores on the fruit and vegetable and traditional English patterns, while lower social deprivation was associated with higher scores for fruit and vegetable, and lower scores for traditional English patterns. All 5 patterns were heritable, with estimates ranging from 41% to 48%. Among individual dietary components, a strongly heritable component was identified for garlic (46%), coffee (41%), fruit and vegetable sources (49%), and red meat (39%). Our results indicate that genetic factors have an important influence in determining food choice and dietary habits in Western populations. The relatively high heritability of specific dietary components implicates taste perception as a possible target for future genetic studies.

Food neophobia shows heritable variation in humans.

Food neophobia refers to reluctance to eat unfamiliar foods. We determined the heritability of food neophobia in a family and a twin sample. The family sample consisted of 28 Finnish families (105 females, 50 males, aged 18-78 years, mean age 49 years) and the twin sample of 468 British female twin pairs (211 monozygous and 257 dizygous pairs, aged 17-82 years, mean age 55 years). Food neophobia was measured using the ten-item Food Neophobia Scale (FNS) questionnaire, and its internationally validated six-item modification. The heritability estimate for food neophobia was 69 and 66% in Finnish families (h(2)) and 67 and 66% in British female twins (a(2)+d(2)) using the ten- and six-item versions of the FNS, respectively. The results from both populations suggest that about two thirds of variation in food neophobia is genetically determined.

Genome-wide linkage scan for athlete status in 700 British female DZ twin pairs.

Association studies, comparing elite athletes with sedentary controls, have reported a number of genes that may be related to athlete status. The present study reports the first genome wide linkage scan for athlete status. Subjects were 4488 adult female twins from the TwinsUK Adult Twin Registry (793 monozygotic [MZ] and 1000 dizygotic [DZ] complete twin pairs, and single twins). Athlete status was measured by asking the twins whether they had ever competed in sports and what was the highest level obtained. Twins who had competed at the county or national level were considered elite athletes. Using structural equation modeling in Mx, the heritability of athlete status was estimated at 66%. Seven hundred DZ twin pairs that were successfully genotyped for 1946 markers (736 microsatellites and 1210 SNPs) were included in the linkage analysis. Identical-by-descent probabilities were estimated in Merlin for a 1 cM grid, taking into account the linkage disequilibrium of correlated SNPs. The linkage scan was carried out in Mx using the [Formula: see text]-approach. Suggestive linkages were found on chromosomes 3q22-q24 and 4q31-q34. Both areas converge with findings from previous studies using exercise phenotypes. The peak on 3q22-q24 was found at the SLC9A9 gene. The region 4q31-q34 overlaps with the region for which suggestive linkages were found in two previous linkage studies for physical fitness (FABP2 gene; Bouchard et al., 2000) and physical activity (UCP1 gene; Simonen et al., 2003). Future association studies should further clarify the possible role of these genes in athlete status.

Genetic influences on motion sickness susceptibility in adult women: a classical twin study.

BACKGROUND: Motion sickness is a common and potentially debilitating condition that characteristically occurs in situations of conflicting sensory input. While the precise stimuli that give rise to this trait are increasingly well characterized, the underlying determinants of individual susceptibility to motion sickness remain unclear. This study uses a classical twin design to assess the influence of genetic and environmental factors. METHODS: A postal survey was conducted in an age-matched sample of 3652 monozygotic (MZ) and dizygotic (DZ) adult female twins selected from the TwinsUK Registry. Study participants were asked to complete items from a validated questionnaire relating to their lifetime susceptibility to motion sickness. The relative contribution of genetic and environmental factors to motion sickness susceptibility was assessed using variance components analysis. RESULTS: The response rate to the questionnaire was 78%. Approximately 40% of respondents reported at least moderate susceptibility to motion sickness. The pattern of responses among twins indicated a significant genetic contribution with heritability for a motion sickness factor score estimated as 57% (95% CI: 51%, 63%). The heritability of recalled motion sickness was at its highest in childhood (70% [59%, 80%]) and declined through puberty and the early adult years. DISCUSSION AND CONCLUSIONS: The findings highlight the importance of genetic factors in determining an individual's underlying propensity to motion sickness and should stimulate the search for specific susceptibility genes.

Heritability of the second to fourth digit ratio (2d:4d): A twin study.

The second to fourth finger length ratio (2d:4d) has been the subject of much recent work and is thought to be related to diverse gender and hormone-related traits including sports ability, disease susceptibility, attractiveness and sexuality. It is established in utero and remains constant in adulthood. Familial clustering has been thought to contribute to the development of 2d:4d from early studies but no twin studies exploring heritability have been reported to date. In this study, a sample of 456 female twin pairs (148 monozygotic [MZ], 308 dizygotic [DZ]) aged 18 to 79 years was used to estimate the heritability of 2d:4d for the right and left hands. Finger lengths were derived from hand x-rays. Variance components analysis was used to estimate and contrast genetic and environmental effects on this phenotype. The mean 2d:4d was 0.92 (SD = 0.001) for both hands. The MZ intraclass correlation was higher than in DZ (.66 vs. .35 for right 2d:4d, and .71 vs. .37 for left 2d:4d). The best fit model included additive polygenic and unique environmental effects ('AE' model), with no significant common environmental effects detected. Heritability was estimated to be approximately 66% for 2d:4d (95% confidence interval 0.5-0.78). These results suggest a substantial genetic contribution to the determination of this hormonally related skeletal ratio in women, which could be more influential than the effects of common prenatal environmental factors. However the current study design does not preclude the possibility of confounding between heritability estimates and unobserved prenatal effects.