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

Nicole M. Warrington, Enisa Shevroja, Gibran Hemani, Pirro G. Hysi, Yunxuan Jiang, Adam Auton, Cindy G. Boer, Massimo Mangino, Carol A. Wang, John P. Kemp, George McMahon, Carolina Medina-Gomez, Martha Hickey, Katerina Trajanoska, Dieter Wolke, M. Arfan Ikram, Grant W. Montgomery, Janine F. Felix, Margaret J. Wright, David A. Mackey & 11 others Vincent W. Jaddoe, Nicholas G. Martin, Joyce Y. Tung, George Davey Smith, Craig E. Pennell, Tim D. Spector, Joyce van Meurs, Fernando Rivadeneira, Sarah E. Medland, David M. Evans, 23and Me Research Team The 23and Me Research Team

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 sexspecific 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 (b=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.

Original languageEnglish
Pages (from-to)2025-2038
Number of pages14
JournalHuman Molecular Genetics
Volume27
Issue number11
DOIs
Publication statusPublished - 1 Jun 2018

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Genome-Wide Association Study
Fingers
Testosterone
Biomarkers
Sample Size
Androgens
Sex Hormone-Binding Globulin
Androgen Receptors
Microsatellite Repeats
Meta-Analysis
Population
Genes

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Warrington, N. M., Shevroja, E., Hemani, G., Hysi, P. G., Jiang, Y., Auton, A., ... The 23and Me Research Team, . M. R. T. (2018). Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero. Human Molecular Genetics, 27(11), 2025-2038. https://doi.org/10.1093/hmg/ddy121
Warrington, Nicole M. ; Shevroja, Enisa ; Hemani, Gibran ; Hysi, Pirro G. ; Jiang, Yunxuan ; Auton, Adam ; Boer, Cindy G. ; Mangino, Massimo ; Wang, Carol A. ; Kemp, John P. ; McMahon, George ; Medina-Gomez, Carolina ; Hickey, Martha ; Trajanoska, Katerina ; Wolke, Dieter ; Ikram, M. Arfan ; Montgomery, Grant W. ; Felix, Janine F. ; Wright, Margaret J. ; Mackey, David A. ; Jaddoe, Vincent W. ; Martin, Nicholas G. ; Tung, Joyce Y. ; Smith, George Davey ; Pennell, Craig E. ; Spector, Tim D. ; van Meurs, Joyce ; Rivadeneira, Fernando ; Medland, Sarah E. ; Evans, David M. ; The 23and Me Research Team, 23and Me Research Team. / Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero. In: Human Molecular Genetics. 2018 ; Vol. 27, No. 11. pp. 2025-2038.
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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 sexspecific 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 (b=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.",
author = "Warrington, {Nicole M.} and Enisa Shevroja and Gibran Hemani and Hysi, {Pirro G.} and Yunxuan Jiang and Adam Auton and Boer, {Cindy G.} and Massimo Mangino and Wang, {Carol A.} and Kemp, {John P.} and George McMahon and Carolina Medina-Gomez and Martha Hickey and Katerina Trajanoska and Dieter Wolke and Ikram, {M. Arfan} and Montgomery, {Grant W.} and Felix, {Janine F.} and Wright, {Margaret J.} and Mackey, {David A.} and Jaddoe, {Vincent W.} and Martin, {Nicholas G.} and Tung, {Joyce Y.} and Smith, {George Davey} and Pennell, {Craig E.} and Spector, {Tim D.} and {van Meurs}, Joyce and Fernando Rivadeneira and Medland, {Sarah E.} and Evans, {David M.} and {The 23and Me Research Team}, {23and Me Research Team}",
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Warrington, NM, Shevroja, E, Hemani, G, Hysi, PG, Jiang, Y, Auton, A, Boer, CG, Mangino, M, Wang, CA, Kemp, JP, McMahon, G, Medina-Gomez, C, Hickey, M, Trajanoska, K, Wolke, D, Ikram, MA, Montgomery, GW, Felix, JF, Wright, MJ, Mackey, DA, Jaddoe, VW, Martin, NG, Tung, JY, Smith, GD, Pennell, CE, Spector, TD, van Meurs, J, Rivadeneira, F, Medland, SE, Evans, DM & The 23and Me Research Team, MRT 2018, 'Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero' Human Molecular Genetics, vol. 27, no. 11, pp. 2025-2038. https://doi.org/10.1093/hmg/ddy121

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.; Shevroja, Enisa; Hemani, Gibran; Hysi, Pirro G.; Jiang, Yunxuan; Auton, Adam; Boer, Cindy G.; Mangino, Massimo; Wang, Carol A.; Kemp, John P.; McMahon, George; Medina-Gomez, Carolina; Hickey, Martha; Trajanoska, Katerina; Wolke, Dieter; Ikram, M. Arfan; Montgomery, Grant W.; Felix, Janine F.; Wright, Margaret J.; Mackey, David A.; Jaddoe, Vincent W.; Martin, Nicholas G.; Tung, Joyce Y.; Smith, George Davey; Pennell, Craig E.; Spector, Tim D.; van Meurs, Joyce; Rivadeneira, Fernando; Medland, Sarah E.; Evans, David M.; The 23and Me Research Team, 23and Me Research Team.

In: Human Molecular Genetics, Vol. 27, No. 11, 01.06.2018, p. 2025-2038.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association study identifies nine novel loci for 2D:4D finger ratio, a putative retrospective biomarker of testosterone exposure in utero

AU - Warrington, Nicole M.

AU - Shevroja, Enisa

AU - Hemani, Gibran

AU - Hysi, Pirro G.

AU - Jiang, Yunxuan

AU - Auton, Adam

AU - Boer, Cindy G.

AU - Mangino, Massimo

AU - Wang, Carol A.

AU - Kemp, John P.

AU - McMahon, George

AU - Medina-Gomez, Carolina

AU - Hickey, Martha

AU - Trajanoska, Katerina

AU - Wolke, Dieter

AU - Ikram, M. Arfan

AU - Montgomery, Grant W.

AU - Felix, Janine F.

AU - Wright, Margaret J.

AU - Mackey, David A.

AU - Jaddoe, Vincent W.

AU - Martin, Nicholas G.

AU - Tung, Joyce Y.

AU - Smith, George Davey

AU - Pennell, Craig E.

AU - Spector, Tim D.

AU - van Meurs, Joyce

AU - Rivadeneira, Fernando

AU - Medland, Sarah E.

AU - Evans, David M.

AU - The 23and Me Research Team, 23and Me Research Team

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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 sexspecific 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 (b=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.

AB - 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 sexspecific 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 (b=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.

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U2 - 10.1093/hmg/ddy121

DO - 10.1093/hmg/ddy121

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JO - Human Molecular Genetics

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SN - 0964-6906

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