Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight

Jessica Tyrrell; Rebecca C Richmond; Tom M Palmer; Bjarke Feenstra; Janani Rangarajan; Sarah Metrustry; Alana Cavadino; Lavinia Paternoster; Loren L Armstrong; N Maneka G De Silva; Andrew R Wood; Momoko Horikoshi; Frank Geller; Ronny Myhre; Jonathan P Bradfield; Eskil Kreiner-Møller; Ville Huikari; Jodie N Painter; Jouke Jan Hottenga; Catherine Allard; Diane J Berry; Luigi Bouchard; Shikta Das; David M Evans; Hakon Hakonarson; M Geoffrey Hayes; Jani Heikkinen; Albert Hofman; Bridget A Knight; Penelope A Lind; Mark I McCarthy; George McMahon; Sarah E. Medland; Mads Melbye; Andrew P Morris; Michael Nodzenski; Christoph Reichetzeder; Susan M Ring; Sylvain Sebert; Verena Sengpiel; Thorkild I A Sørensen; Gonneke Willemsen; Eco J C de Geus; Nicholas G. Martin; Tim D Spector; Christine Power; Marjo-Riitta Järvelin; Hans Bisgaard; Struan F A Grant; Ellen A Nohr; Early Growth Genetics (EGG) Consortium

doi:10.1001/jama.2016.1975

Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight

Jessica Tyrrell, Rebecca C Richmond, Tom M Palmer, Bjarke Feenstra, Janani Rangarajan, Sarah Metrustry, Alana Cavadino, Lavinia Paternoster, Loren L Armstrong, N Maneka G De Silva, Andrew R Wood, Momoko Horikoshi, Frank Geller, Ronny Myhre, Jonathan P Bradfield, Eskil Kreiner-Møller, Ville Huikari, Jodie N Painter, Jouke Jan Hottenga, Catherine AllardDiane J Berry, Luigi Bouchard, Shikta Das, David M Evans, Hakon Hakonarson, M Geoffrey Hayes, Jani Heikkinen, Albert Hofman, Bridget A Knight, Penelope A Lind, Mark I McCarthy, George McMahon, Sarah E. Medland, Mads Melbye, Andrew P Morris, Michael Nodzenski, Christoph Reichetzeder, Susan M Ring, Sylvain Sebert, Verena Sengpiel, Thorkild I A Sørensen, Gonneke Willemsen, Eco J C de Geus, Nicholas G. Martin, Tim D Spector, Christine Power, Marjo-Riitta Järvelin, Hans Bisgaard, Struan F A Grant, Ellen A Nohr, Early Growth Genetics (EGG) Consortium

125 Citationer (Scopus)

Abstract

IMPORTANCE: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.

OBJECTIVE: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.

DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.

EXPOSURES: Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.

MAIN OUTCOME AND MEASURE: Offspring birth weight from 18 studies.

RESULTS: Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.

CONCLUSIONS AND RELEVANCE: In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

Originalsprog	Engelsk
Tidsskrift	J A M A: The Journal of the American Medical Association
Vol/bind	315
Udgave nummer	11
Sider (fra-til)	1129-40
Antal sider	12
ISSN	0098-7484
DOI	https://doi.org/10.1001/jama.2016.1975
Status	Udgivet - 15 mar. 2016

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10.1001/jama.2016.1975

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Tyrrell, J., Richmond, R. C., Palmer, T. M., Feenstra, B., Rangarajan, J., Metrustry, S., Cavadino, A., Paternoster, L., Armstrong, L. L., De Silva, N. M. G., Wood, A. R., Horikoshi, M., Geller, F., Myhre, R., Bradfield, J. P., Kreiner-Møller, E., Huikari, V., Painter, J. N., Hottenga, J. J., ... Early Growth Genetics (EGG) Consortium (2016). Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight. J A M A: The Journal of the American Medical Association, 315(11), 1129-40. https://doi.org/10.1001/jama.2016.1975

Tyrrell, J, Richmond, RC, Palmer, TM, Feenstra, B, Rangarajan, J, Metrustry, S, Cavadino, A, Paternoster, L, Armstrong, LL, De Silva, NMG, Wood, AR, Horikoshi, M, Geller, F, Myhre, R, Bradfield, JP, Kreiner-Møller, E, Huikari, V, Painter, JN, Hottenga, JJ, Allard, C, Berry, DJ, Bouchard, L, Das, S, Evans, DM, Hakonarson, H, Hayes, MG, Heikkinen, J, Hofman, A, Knight, BA, Lind, PA, McCarthy, MI, McMahon, G, Medland, SE, Melbye, M, Morris, AP, Nodzenski, M, Reichetzeder, C, Ring, SM, Sebert, S, Sengpiel, V, Sørensen, TIA, Willemsen, G, de Geus, EJC, Martin, NG, Spector, TD, Power, C, Järvelin, M-R, Bisgaard, H, Grant, SFA, Nohr, EA & Early Growth Genetics (EGG) Consortium 2016, 'Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight', J A M A: The Journal of the American Medical Association, bind 315, nr. 11, s. 1129-40. https://doi.org/10.1001/jama.2016.1975

@article{a258f799cec349a8906b101b9ac95a86,

title = "Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight",

abstract = "IMPORTANCE: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.OBJECTIVE: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.EXPOSURES: Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.MAIN OUTCOME AND MEASURE: Offspring birth weight from 18 studies.RESULTS: Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.CONCLUSIONS AND RELEVANCE: In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.",

keywords = "Adult, Birth Weight, Blood Glucose, Blood Pressure, Body Mass Index, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Fasting, Female, Genotype, Humans, Infant, Newborn, Mendelian Randomization Analysis, Obesity, Polymorphism, Single Nucleotide, Pregnancy, Triglycerides, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

author = "Jessica Tyrrell and Richmond, {Rebecca C} and Palmer, {Tom M} and Bjarke Feenstra and Janani Rangarajan and Sarah Metrustry and Alana Cavadino and Lavinia Paternoster and Armstrong, {Loren L} and {De Silva}, {N Maneka G} and Wood, {Andrew R} and Momoko Horikoshi and Frank Geller and Ronny Myhre and Bradfield, {Jonathan P} and Eskil Kreiner-M{\o}ller and Ville Huikari and Painter, {Jodie N} and Hottenga, {Jouke Jan} and Catherine Allard and Berry, {Diane J} and Luigi Bouchard and Shikta Das and Evans, {David M} and Hakon Hakonarson and Hayes, {M Geoffrey} and Jani Heikkinen and Albert Hofman and Knight, {Bridget A} and Lind, {Penelope A} and McCarthy, {Mark I} and George McMahon and Medland, {Sarah E.} and Mads Melbye and Morris, {Andrew P} and Michael Nodzenski and Christoph Reichetzeder and Ring, {Susan M} and Sylvain Sebert and Verena Sengpiel and S{\o}rensen, {Thorkild I A} and Gonneke Willemsen and {de Geus}, {Eco J C} and Martin, {Nicholas G.} and Spector, {Tim D} and Christine Power and Marjo-Riitta J{\"a}rvelin and Hans Bisgaard and Grant, {Struan F A} and Nohr, {Ellen A} and {Early Growth Genetics (EGG) Consortium}",

year = "2016",

month = mar,

day = "15",

doi = "10.1001/jama.2016.1975",

language = "English",

volume = "315",

pages = "1129--40",

journal = "J A M A: The Journal of the American Medical Association",

issn = "0098-7484",

publisher = "American Medical Association",

number = "11",

}

TY - JOUR

T1 - Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight

AU - Tyrrell, Jessica

AU - Richmond, Rebecca C

AU - Palmer, Tom M

AU - Feenstra, Bjarke

AU - Rangarajan, Janani

AU - Metrustry, Sarah

AU - Cavadino, Alana

AU - Paternoster, Lavinia

AU - Armstrong, Loren L

AU - De Silva, N Maneka G

AU - Wood, Andrew R

AU - Horikoshi, Momoko

AU - Geller, Frank

AU - Myhre, Ronny

AU - Bradfield, Jonathan P

AU - Kreiner-Møller, Eskil

AU - Huikari, Ville

AU - Painter, Jodie N

AU - Hottenga, Jouke Jan

AU - Allard, Catherine

AU - Berry, Diane J

AU - Bouchard, Luigi

AU - Das, Shikta

AU - Evans, David M

AU - Hakonarson, Hakon

AU - Hayes, M Geoffrey

AU - Heikkinen, Jani

AU - Hofman, Albert

AU - Knight, Bridget A

AU - Lind, Penelope A

AU - McCarthy, Mark I

AU - McMahon, George

AU - Medland, Sarah E.

AU - Melbye, Mads

AU - Morris, Andrew P

AU - Nodzenski, Michael

AU - Reichetzeder, Christoph

AU - Ring, Susan M

AU - Sebert, Sylvain

AU - Sengpiel, Verena

AU - Sørensen, Thorkild I A

AU - Willemsen, Gonneke

AU - de Geus, Eco J C

AU - Martin, Nicholas G.

AU - Spector, Tim D

AU - Power, Christine

AU - Järvelin, Marjo-Riitta

AU - Bisgaard, Hans

AU - Grant, Struan F A

AU - Nohr, Ellen A

AU - Early Growth Genetics (EGG) Consortium

PY - 2016/3/15

Y1 - 2016/3/15

N2 - IMPORTANCE: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.OBJECTIVE: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.EXPOSURES: Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.MAIN OUTCOME AND MEASURE: Offspring birth weight from 18 studies.RESULTS: Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.CONCLUSIONS AND RELEVANCE: In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

AB - IMPORTANCE: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.OBJECTIVE: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.EXPOSURES: Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.MAIN OUTCOME AND MEASURE: Offspring birth weight from 18 studies.RESULTS: Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.CONCLUSIONS AND RELEVANCE: In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

KW - Adult

KW - Birth Weight

KW - Blood Glucose

KW - Blood Pressure

KW - Body Mass Index

KW - Diabetes Mellitus, Type 2

KW - European Continental Ancestry Group

KW - Fasting

KW - Female

KW - Genotype

KW - Humans

KW - Infant, Newborn

KW - Mendelian Randomization Analysis

KW - Obesity

KW - Polymorphism, Single Nucleotide

KW - Pregnancy

KW - Triglycerides

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1001/jama.2016.1975

DO - 10.1001/jama.2016.1975

M3 - Journal article

C2 - 26978208

SN - 0098-7484

VL - 315

SP - 1129

EP - 1140

JO - J A M A: The Journal of the American Medical Association

JF - J A M A: The Journal of the American Medical Association

IS - 11

ER -

Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight

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