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Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero.

ABSTRACT: The ratio of the length of the index finger to that of the ring finger (2D:4D) is sexually dimorphic and is commonly used as a non-invasive biomarker of prenatal androgen exposure. Most association studies of 2D:4D ratio with a diverse range of sex-specific traits have typically involved small sample sizes and have been difficult to replicate, raising questions around the utility and precise meaning of the measure. In the largest genome-wide association meta-analysis of 2D:4D ratio to date (N?=?15 661, with replication N?=?75 821), we identified 11 loci (9 novel) explaining 3.8% of the variance in mean 2D:4D ratio. We also found weak evidence for association (??=?0.06; P?=?0.02) between 2D:4D ratio and sensitivity to testosterone [length of the CAG microsatellite repeat in the androgen receptor (AR) gene] in females only. Furthermore, genetic variants associated with (adult) testosterone levels and/or sex hormone-binding globulin were not associated with 2D:4D ratio in our sample. Although we were unable to find strong evidence from our genetic study to support the hypothesis that 2D:4D ratio is a direct biomarker of prenatal exposure to androgens in healthy individuals, our findings do not explicitly exclude this possibility, and pathways involving testosterone may become apparent as the size of the discovery sample increases further. Our findings provide new insight into the underlying biology shaping 2D:4D variation in the general population.

SUBMITTER: Warrington NM

PROVIDER: S-EPMC5961159 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero.

Warrington Nicole M NM Shevroja Enisa E Hemani Gibran G Hysi Pirro G PG Jiang Yunxuan Y Auton Adam A Boer Cindy G CG Mangino Massimo M Wang Carol A CA Kemp John P JP McMahon George G Medina-Gomez Carolina C Hickey Martha M Trajanoska Katerina K Wolke Dieter D Ikram M Arfan MA Montgomery Grant W GW Felix Janine F JF Wright Margaret J MJ Mackey David A DA Jaddoe Vincent W VW Martin Nicholas G NG Tung Joyce Y JY Davey Smith George G Pennell Craig E CE Spector Tim D TD van Meurs Joyce J Rivadeneira Fernando F Medland Sarah E SE Evans David M DM

Human molecular genetics 20180601 11

The ratio of the length of the index finger to that of the ring finger (2D:4D) is sexually dimorphic and is commonly used as a non-invasive biomarker of prenatal androgen exposure. Most association studies of 2D:4D ratio with a diverse range of sex-specific traits have typically involved small sample sizes and have been difficult to replicate, raising questions around the utility and precise meaning of the measure. In the largest genome-wide association meta-analysis of 2D:4D ratio to date (N = ...[more]

PMID: 29659830

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Project description:ObjectivesTo explore whether random chance, weak research methodology, or inappropriate reporting can lead to claims of statistically significant (yet, biologically meaningless) biomarker associations, using as a model the relation between a common surrogate of prenatal testosterone exposure, second-to-fourth digit ratio (2D:4D), and a random indicator of good luck.DesignCross sectional study.SettingUniversity sports performance laboratory in the United States. Data were collected from May 2015 to February 2017.Participants176 adults (74 women, 102 men), including university students, faculty, and staff with no history of injuries, disease, or medical conditions that would affect digit length.Main outcome measures2D:4D, body composition parameters potentially influenced by androgens (bone mineral content, bone mineral density, body fat percentage), and good luck (using poker hands from randomly selected playing cards as a surrogate).Results2D:4D significantly correlated with select body composition parameters (Spearman's r s range -0.26 to 0.23; P<0.05), but the correlations varied by sex, participant hand measured, and the method of measuring 2D:4D (by photocopy or radiography). However, the strongest correlation observed was between right hand 2D:4D in men measured by radiograph and poker hand rank (r s=0.28, P=0.004).ConclusionsGreater prenatal exposure to testosterone, as estimated by a lower 2D:4D, significantly increases good luck in adulthood, and also modulates body composition (albeit to a lesser degree). While these findings are consistent with a wealth of research reporting that 2D:4D is related to many seemingly disparate outcomes, they are not meant to provide confirmatory evidence that 2D:4D is a universal biomarker of nearly everything. Instead, the associations between 2D:4D and good luck are simply due to chance, and provide a "handy" example of the reproducibility crisis within medical and scientific research. Biologically sound hypotheses, pre-registration of trials, strong methodological and statistical analyses, transparent reporting of negative results, and unbiased interpretation of data are all necessary for biomarker studies and other areas of clinical research.

Project description:BackgroundDespite the global increase in the prevalence of autism spectrum disorders (ASD), relevant research studies are lacking in Brunei Darussalam. Various studies have shown a significant association between a lowered 2D:4D ratio (ratio of second digit/index finger to the fourth digit/ring finger) and ASD, making it one of the potential phenotypic biomarkers for early detection of autism, which is important for early intervention and management.ObjectiveThe objective of this study is to explore the association between 2D:4D ratio and ASD in Brunei Darussalam, as a potential tool to complement early ASD diagnosis.MethodsWe conducted a case-control study comprising 28 ASD and 62 typically developing (TD) children in the case and control group, respectively (age range: 3-11 years old; median age: 6 years old). Median 2D:4D ratios were measured, compared and analysed between the two groups. Logistic regression models were used to explore potential associations between the median 2D:4D ratio and ASD in respective gender, for both left and right hands, independently.ResultsOur study shows that the median 2D:4D ratio of left hand in ASD males is significantly lower than those in TD males, after adjusting for ethnicity and age [Odds Ratio (OR) = 0.57 (95% Confidence Interval (CI): 0.31-0.96); p = 0.044]. For females, there is no association of ASD with the median left hand 2D:4D ratio [OR = 3.09 (95% CI: 0.98-19.86); p = 0.144] or the median right hand 2D:4D ratio [OR = 1.23 (95% CI: 0.42-3.88); p = 0.702]. Our study also shows a significant positive correlation and/or a reduced asymmetry between the average 2D:4D ratio of left hands and right hands in ASD males (Pearson's correlation (r) = 0.48; 95% CI: 0.076-0.75, p = 0.023).ConclusionsThere is significant association between a lowered median 2D:4D ratio of the left hand (in males only) and ASD diagnosis. Once validated in a larger sample size, a lowered median 2D:4D ratio on the left hand may be a potential tool to complement ASD diagnosis for males in our study population. There is no association between the median 2D:4D ratio (left or right hands) and ASD in females, which could be due to the small female sample size and/or the possibility of different aetiology for ASD in females. Reduced asymmetry between the average 2D:4D ratio of left and right hands observed in ASD males only (not in ASD females) also suggests the importance of considering gender-specific biomarkers for ASD diagnosis.

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Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero.

Publications

Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero.

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