Altmaier, E

Antoniou, AC

Arriola, L

Balkau, B

Barbieri, C

Barricarte, A

Barroso, I

Boeing, H

Boerwinkle, E

Buring, JE

Campbell, A

Chasman, DI

Coviello, AD

Crisponi, L

Cucca, F

Day, FR

Deary, IJ

Deloukas, P

Demerath, EW

Dunning, AM

Easton, DF

Elks, CE

Esko, T

Forouhi, NG

Franceschini, N

Franks, PW

Gandin, I

Gonzalez, C

Grioni, S

Grove, ML

Gudbjartsson, DF

Hayward, C

He, C

Hinds, DA

Hocking, LJ

Hofman, A

Hu, FB

Huang, J

Huffman, JE

Jackson, RD

Kaaks, R

Karasik, D

Kerrison, ND

Key, TJ

Kriebel, J

Lange, EM

Lange, LA

Langenberg, C

Li, X

Liu, S

Luan, J

Lunetta, KL

Maegi, R

McCarthy, MI

McIntosh, AM

Metspalu, A

Mihailov, E

Morrison, AC

Murabito, JM

Murray, A

Navarro, C

Nilsson, PM

Ong, KK

Overvad, K

Padmanabhan, S

Palli, D

Panico, S

Pennell, CE

Perry, JRB

Pirie, A

Polasek, O

Porcu, E

Porteous, D

Ramon Quiros, J

Reiner, AP

Riboli, E

Ridker, PM

Rivadeneira, F

Robino, A

Rolandsson, O

Rose, LM

Rudan, I

Ruth, KS

Sacerdote, C

Sala, CF

Sanchez, M-J

Schick, UM

Schlessinger, D

Scott, RA

Sharp, SJ

Sims, M

Slimani, N

Smith, BH

Stefansson, K

Stoeckl, D

Stolk, L

Strauch, K

Streeten, EA

Sulem, P

Teumer, A

Nature Communications

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P&lt;5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P = 2.8 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the &apos;missing heritability&apos; of this complex trait

Tung, JY

He, CY

Stolk, Lisette

Thompson, DJ

Traglia, M

Wang, CA

Yerges-Armstrong, LM

Hofman, Bert

Huang, JY

Lange, Edmee

Luan, JA

Magi, R

Rivadeneira, Fernando

Stockl, D

Visser, Jenny

Volker, U

Vozzi, D

Wilson, JG

Zygmunt, M

Liu, SM (Simin)

Toniolo, D

Uitterlinden, André

Ulivi, S

Volzke, H

Wareham, NJ

Wellons, M

Thorsteinsdottir, U

EUR Research Repository

English

Rare coding variants and X-linked loci associated with age at menarche

More than 100 loci have been identified for age at menarche by genome-wide association
studies; however, collectively these explain only B3% of the trait variance. Here we test two
overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding
variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/
LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies
0.08–4.6%; effect sizes 0.08–1.25 years per allele; Po5  10  8). In addition, we
identify common X-chromosome loci at IGSF1 (rs762080, P ¼ 9.4  10  13) and FAAH2
(rs5914101, P ¼ 4.9  10  10). Highlighted genes implicate cellular energy homeostasis, posttranscriptional
gene silencing and fatty-acid amide signalling. A frequently reported mutation
in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-
year-later menarche (P ¼ 2.8  10  11), illustrating the utility of population studies to estimate
the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain
B0.5% variance, indicating that these overlooked sources of variation do not substantially
explain the ‘missing heritability’ of this complex trait

Rare coding variants and X-linked loci associated with age at menarche

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