Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses

Yi-Qian Sun; Stephen Burgess; James R Staley; Angela M Wood; Steven Bell; Stephen K Kaptoge; Qi Guo; Thomas R Bolton; Amy M Mason; Adam S Butterworth; Emanuele Di Angelantonio; Gunnhild Å Vie; Johan H Bjørngaard; Jonas Minet Kinge; Yue Chen; Xiao-Mei Mai

doi:10.1136/bmj.l1042

Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses

Yi-Qian Sun, Stephen Burgess, James R Staley, Angela M Wood, Steven Bell, Stephen K Kaptoge, Qi Guo, Thomas R Bolton, Amy M Mason, Adam S Butterworth, Emanuele Di Angelantonio, Gunnhild Å Vie, Johan H Bjørngaard, Jonas Minet Kinge, Yue Chen, Xiao-Mei Mai

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Abstract

OBJECTIVE: To investigate the shape of the causal relation between body mass index (BMI) and mortality.

DESIGN: Linear and non-linear mendelian randomisation analyses.

SETTING: Nord-Trøndelag Health (HUNT) Study (Norway) and UK Biobank (United Kingdom).

PARTICIPANTS: Middle to early late aged participants of European descent: 56 150 from the HUNT Study and 366 385 from UK Biobank.

MAIN OUTCOME MEASURES: All cause and cause specific (cardiovascular, cancer, and non-cardiovascular non-cancer) mortality.

RESULTS: 12 015 and 10 344 participants died during a median of 18.5 and 7.0 years of follow-up in the HUNT Study and UK Biobank, respectively. Linear mendelian randomisation analyses indicated an overall positive association between genetically predicted BMI and the risk of all cause mortality. An increase of 1 unit in genetically predicted BMI led to a 5% (95% confidence interval 1% to 8%) higher risk of mortality in overweight participants (BMI 25.0-29.9) and a 9% (4% to 14%) higher risk of mortality in obese participants (BMI ≥30.0) but a 34% (16% to 48%) lower risk in underweight (BMI <18.5) and a 14% (-1% to 27%) lower risk in low normal weight participants (BMI 18.5-19.9). Non-linear mendelian randomisation indicated a J shaped relation between genetically predicted BMI and the risk of all cause mortality, with the lowest risk at a BMI of around 22-25 for the overall sample. Subgroup analyses by smoking status, however, suggested an always-increasing relation of BMI with mortality in never smokers and a J shaped relation in ever smokers.

CONCLUSIONS: The previously observed J shaped relation between BMI and risk of all cause mortality appears to have a causal basis, but subgroup analyses by smoking status revealed that the BMI-mortality relation is likely comprised of at least two distinct curves, rather than one J shaped relation. An increased risk of mortality for being underweight was only evident in ever smokers.

Original language	English
Article number	l1042
Number of pages	10
Journal	BMJ
Volume	364
DOIs	https://doi.org/10.1136/bmj.l1042
Publication status	Published - 26 Mar 2019

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Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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Sun, Y.-Q., Burgess, S., Staley, J. R., Wood, A. M., Bell, S., Kaptoge, S. K., Guo, Q., Bolton, T. R., Mason, A. M., Butterworth, A. S., Di Angelantonio, E., Vie, G. Å., Bjørngaard, J. H., Kinge, J. M., Chen, Y., & Mai, X.-M. (2019). Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses. BMJ, 364, Article l1042. https://doi.org/10.1136/bmj.l1042

@article{ec4b33a2e8144337a1db9b4433edb013,

title = "Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses",

abstract = "OBJECTIVE: To investigate the shape of the causal relation between body mass index (BMI) and mortality.DESIGN: Linear and non-linear mendelian randomisation analyses.SETTING: Nord-Tr{\o}ndelag Health (HUNT) Study (Norway) and UK Biobank (United Kingdom).PARTICIPANTS: Middle to early late aged participants of European descent: 56 150 from the HUNT Study and 366 385 from UK Biobank.MAIN OUTCOME MEASURES: All cause and cause specific (cardiovascular, cancer, and non-cardiovascular non-cancer) mortality.RESULTS: 12 015 and 10 344 participants died during a median of 18.5 and 7.0 years of follow-up in the HUNT Study and UK Biobank, respectively. Linear mendelian randomisation analyses indicated an overall positive association between genetically predicted BMI and the risk of all cause mortality. An increase of 1 unit in genetically predicted BMI led to a 5% (95% confidence interval 1% to 8%) higher risk of mortality in overweight participants (BMI 25.0-29.9) and a 9% (4% to 14%) higher risk of mortality in obese participants (BMI ≥30.0) but a 34% (16% to 48%) lower risk in underweight (BMI <18.5) and a 14% (-1% to 27%) lower risk in low normal weight participants (BMI 18.5-19.9). Non-linear mendelian randomisation indicated a J shaped relation between genetically predicted BMI and the risk of all cause mortality, with the lowest risk at a BMI of around 22-25 for the overall sample. Subgroup analyses by smoking status, however, suggested an always-increasing relation of BMI with mortality in never smokers and a J shaped relation in ever smokers.CONCLUSIONS: The previously observed J shaped relation between BMI and risk of all cause mortality appears to have a causal basis, but subgroup analyses by smoking status revealed that the BMI-mortality relation is likely comprised of at least two distinct curves, rather than one J shaped relation. An increased risk of mortality for being underweight was only evident in ever smokers.",

author = "Yi-Qian Sun and Stephen Burgess and Staley, {James R} and Wood, {Angela M} and Steven Bell and Kaptoge, {Stephen K} and Qi Guo and Bolton, {Thomas R} and Mason, {Amy M} and Butterworth, {Adam S} and {Di Angelantonio}, Emanuele and Vie, {Gunnhild {\AA}} and Bj{\o}rngaard, {Johan H} and Kinge, {Jonas Minet} and Yue Chen and Xiao-Mei Mai",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.",

year = "2019",

month = mar,

day = "26",

doi = "10.1136/bmj.l1042",

language = "English",

volume = "364",

journal = "BMJ",

issn = "0959-8138",

publisher = "BMJ Publishing Group",

}

Sun, Y-Q, Burgess, S, Staley, JR, Wood, AM, Bell, S, Kaptoge, SK, Guo, Q, Bolton, TR, Mason, AM, Butterworth, AS, Di Angelantonio, E, Vie, GÅ, Bjørngaard, JH, Kinge, JM, Chen, Y & Mai, X-M 2019, 'Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses', BMJ, vol. 364, l1042. https://doi.org/10.1136/bmj.l1042

TY - JOUR

T1 - Body mass index and all cause mortality in HUNT and UK Biobank studies

T2 - linear and non-linear mendelian randomisation analyses

AU - Sun, Yi-Qian

AU - Burgess, Stephen

AU - Staley, James R

AU - Wood, Angela M

AU - Bell, Steven

AU - Kaptoge, Stephen K

AU - Guo, Qi

AU - Bolton, Thomas R

AU - Mason, Amy M

AU - Butterworth, Adam S

AU - Di Angelantonio, Emanuele

AU - Vie, Gunnhild Å

AU - Bjørngaard, Johan H

AU - Kinge, Jonas Minet

AU - Chen, Yue

AU - Mai, Xiao-Mei

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PY - 2019/3/26

Y1 - 2019/3/26

N2 - OBJECTIVE: To investigate the shape of the causal relation between body mass index (BMI) and mortality.DESIGN: Linear and non-linear mendelian randomisation analyses.SETTING: Nord-Trøndelag Health (HUNT) Study (Norway) and UK Biobank (United Kingdom).PARTICIPANTS: Middle to early late aged participants of European descent: 56 150 from the HUNT Study and 366 385 from UK Biobank.MAIN OUTCOME MEASURES: All cause and cause specific (cardiovascular, cancer, and non-cardiovascular non-cancer) mortality.RESULTS: 12 015 and 10 344 participants died during a median of 18.5 and 7.0 years of follow-up in the HUNT Study and UK Biobank, respectively. Linear mendelian randomisation analyses indicated an overall positive association between genetically predicted BMI and the risk of all cause mortality. An increase of 1 unit in genetically predicted BMI led to a 5% (95% confidence interval 1% to 8%) higher risk of mortality in overweight participants (BMI 25.0-29.9) and a 9% (4% to 14%) higher risk of mortality in obese participants (BMI ≥30.0) but a 34% (16% to 48%) lower risk in underweight (BMI <18.5) and a 14% (-1% to 27%) lower risk in low normal weight participants (BMI 18.5-19.9). Non-linear mendelian randomisation indicated a J shaped relation between genetically predicted BMI and the risk of all cause mortality, with the lowest risk at a BMI of around 22-25 for the overall sample. Subgroup analyses by smoking status, however, suggested an always-increasing relation of BMI with mortality in never smokers and a J shaped relation in ever smokers.CONCLUSIONS: The previously observed J shaped relation between BMI and risk of all cause mortality appears to have a causal basis, but subgroup analyses by smoking status revealed that the BMI-mortality relation is likely comprised of at least two distinct curves, rather than one J shaped relation. An increased risk of mortality for being underweight was only evident in ever smokers.

AB - OBJECTIVE: To investigate the shape of the causal relation between body mass index (BMI) and mortality.DESIGN: Linear and non-linear mendelian randomisation analyses.SETTING: Nord-Trøndelag Health (HUNT) Study (Norway) and UK Biobank (United Kingdom).PARTICIPANTS: Middle to early late aged participants of European descent: 56 150 from the HUNT Study and 366 385 from UK Biobank.MAIN OUTCOME MEASURES: All cause and cause specific (cardiovascular, cancer, and non-cardiovascular non-cancer) mortality.RESULTS: 12 015 and 10 344 participants died during a median of 18.5 and 7.0 years of follow-up in the HUNT Study and UK Biobank, respectively. Linear mendelian randomisation analyses indicated an overall positive association between genetically predicted BMI and the risk of all cause mortality. An increase of 1 unit in genetically predicted BMI led to a 5% (95% confidence interval 1% to 8%) higher risk of mortality in overweight participants (BMI 25.0-29.9) and a 9% (4% to 14%) higher risk of mortality in obese participants (BMI ≥30.0) but a 34% (16% to 48%) lower risk in underweight (BMI <18.5) and a 14% (-1% to 27%) lower risk in low normal weight participants (BMI 18.5-19.9). Non-linear mendelian randomisation indicated a J shaped relation between genetically predicted BMI and the risk of all cause mortality, with the lowest risk at a BMI of around 22-25 for the overall sample. Subgroup analyses by smoking status, however, suggested an always-increasing relation of BMI with mortality in never smokers and a J shaped relation in ever smokers.CONCLUSIONS: The previously observed J shaped relation between BMI and risk of all cause mortality appears to have a causal basis, but subgroup analyses by smoking status revealed that the BMI-mortality relation is likely comprised of at least two distinct curves, rather than one J shaped relation. An increased risk of mortality for being underweight was only evident in ever smokers.

U2 - 10.1136/bmj.l1042

DO - 10.1136/bmj.l1042

M3 - Article (Academic Journal)

C2 - 30957776

SN - 0959-8138

VL - 364

JO - BMJ

JF - BMJ

M1 - l1042

ER -

Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses

Abstract

Bibliographical note

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