Abstract
Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5×10 -8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Human Molecular Genetics |
| Vol/bind | 27 |
| Udgave nummer | 4 |
| Sider (fra-til) | 742-756 |
| Antal sider | 15 |
| ISSN | 0964-6906 |
| DOI | |
| Status | Udgivet - 2018 |
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Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics. / Beaumont, Robin N.; Warrington, Nicole M.; Cavadino, Alana; Tyrrell, Jessica; Nodzenski, Michael; Horikoshi, Momoko; Geller, Frank; Myhre, Ronny; Richmond, Rebecca C.; Paternoster, Lavinia; Bradfield, Jonathan P.; Kreiner-Moller, Eskil; Huikari, Ville; Metrustry, Sarah; Lunetta, Kathryn L.; Painter, Jodie N.; Hottenga, Jouke-Jan; Allard, Catherine; Barton, Sheila J.; Espinosa, Ana; Marsh, Julie A.; Potter, Catherine; Zhang, Ge; Ang, Wei; Berry, Diane J.; Bouchard, Luigi; Das, Shikta; Hakonarson, Hakon; Heikkinen, Jani; Helgeland, Oyvind; Hocher, Berthold; Hofman, Albert; Inskip, Hazel M.; Jones, Samuel E.; Kogevinas, Manolis; Lind, Penelope A.; Marullo, Letizia; Medland, Sarah E.; Murray, Anna; Murray, Jeffrey C.; Njolstad, Pal R.; Nohr, Ellen A.; Reichetzeder, Christoph; Ring, Susan M.; Ruth, Katherine S.; Santa-Marina, Loreto; Scholtens, Denise M.; Sebert, Sylvain; Sengpiel, Verena; Tuke, Marcus A.; Vaudel, Marc; Weedon, Michael N.; Willemsen, Gonneke; Wood, Andrew R.; Yaghootkar, Hanieh; Muglia, Louis J.; Bartels, Meike; Relton, Caroline L.; Pennell, Craig E.; Chatzi, Leda; Estivill, Xavier; Holloway, John W.; Boomsma, Dorret I.; Montgomery, Grant W.; Murabito, Joanne M.; Spector, Tim D.; Power, Christine; Jarvelin, Marjo-Ritta; Bisgaard, Hans; Grant, Struan F. A.; Sørensen, Thorkild I. A.; Jaddoe, Vincent W.; Jacobsson, Bo; Melbye, Mads; McCarthy, Mark I.; Hattersley, Andrew T.; Hayes, M. Geoffrey; Frayling, Timothy M.; Hivert, Marie-France; Felix, Janine F.; Hypponen, Elina; Lowe, William L., Jr.; Evans, David M.; Lawlor, Debbie A.; Feenstra, Bjarke; Freathy, Rachel M.
I: Human Molecular Genetics, Bind 27, Nr. 4, 2018, s. 742-756.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
}
TY - JOUR
T1 - Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics
AU - Beaumont, Robin N.
AU - Warrington, Nicole M.
AU - Cavadino, Alana
AU - Tyrrell, Jessica
AU - Nodzenski, Michael
AU - Horikoshi, Momoko
AU - Geller, Frank
AU - Myhre, Ronny
AU - Richmond, Rebecca C.
AU - Paternoster, Lavinia
AU - Bradfield, Jonathan P.
AU - Kreiner-Moller, Eskil
AU - Huikari, Ville
AU - Metrustry, Sarah
AU - Lunetta, Kathryn L.
AU - Painter, Jodie N.
AU - Hottenga, Jouke-Jan
AU - Allard, Catherine
AU - Barton, Sheila J.
AU - Espinosa, Ana
AU - Marsh, Julie A.
AU - Potter, Catherine
AU - Zhang, Ge
AU - Ang, Wei
AU - Berry, Diane J.
AU - Bouchard, Luigi
AU - Das, Shikta
AU - Hakonarson, Hakon
AU - Heikkinen, Jani
AU - Helgeland, Oyvind
AU - Hocher, Berthold
AU - Hofman, Albert
AU - Inskip, Hazel M.
AU - Jones, Samuel E.
AU - Kogevinas, Manolis
AU - Lind, Penelope A.
AU - Marullo, Letizia
AU - Medland, Sarah E.
AU - Murray, Anna
AU - Murray, Jeffrey C.
AU - Njolstad, Pal R.
AU - Nohr, Ellen A.
AU - Reichetzeder, Christoph
AU - Ring, Susan M.
AU - Ruth, Katherine S.
AU - Santa-Marina, Loreto
AU - Scholtens, Denise M.
AU - Sebert, Sylvain
AU - Sengpiel, Verena
AU - Tuke, Marcus A.
AU - Vaudel, Marc
AU - Weedon, Michael N.
AU - Willemsen, Gonneke
AU - Wood, Andrew R.
AU - Yaghootkar, Hanieh
AU - Muglia, Louis J.
AU - Bartels, Meike
AU - Relton, Caroline L.
AU - Pennell, Craig E.
AU - Chatzi, Leda
AU - Estivill, Xavier
AU - Holloway, John W.
AU - Boomsma, Dorret I.
AU - Montgomery, Grant W.
AU - Murabito, Joanne M.
AU - Spector, Tim D.
AU - Power, Christine
AU - Jarvelin, Marjo-Ritta
AU - Bisgaard, Hans
AU - Grant, Struan F. A.
AU - Sørensen, Thorkild I. A.
AU - Jaddoe, Vincent W.
AU - Jacobsson, Bo
AU - Melbye, Mads
AU - McCarthy, Mark I.
AU - Hattersley, Andrew T.
AU - Hayes, M. Geoffrey
AU - Frayling, Timothy M.
AU - Hivert, Marie-France
AU - Felix, Janine F.
AU - Hypponen, Elina
AU - Lowe, William L., Jr.
AU - Evans, David M.
AU - Lawlor, Debbie A.
AU - Feenstra, Bjarke
AU - Freathy, Rachel M.
PY - 2018
Y1 - 2018
N2 - Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5×10 -8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
AB - Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5×10 -8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
U2 - 10.1093/hmg/ddx429
DO - 10.1093/hmg/ddx429
M3 - Journal article
C2 - 29309628
VL - 27
SP - 742
EP - 756
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 4
ER -