Mapping anorexia nervosa genes to clinical phenotypes

Jessica S Johnson; Alanna C Cote; Amanda Dobbyn; Laura G Sloofman; Jiayi Xu; Liam Cotter; Alexander W Charney; Andreas Birgegård; Jennifer Jordan; Martin Kennedy; Mikaél Landén; Sarah L Maguire; Nicholas G Martin; Preben Bo Mortensen; Laura M Thornton; Cynthia M Bulik; Laura M Huckins; Eating Disorders Working Group of the Psychiatric Genomics Consortium

doi:10.1017/S0033291721004554

Mapping anorexia nervosa genes to clinical phenotypes

Jessica S Johnson, Alanna C Cote, Amanda Dobbyn, Laura G Sloofman, Jiayi Xu, Liam Cotter, Alexander W Charney, Andreas Birgegård, Jennifer Jordan, Martin Kennedy, Mikaél Landén, Sarah L Maguire, Nicholas G Martin, Preben Bo Mortensen, Laura M Thornton, Cynthia M Bulik, Laura M Huckins, Eating Disorders Working Group of the Psychiatric Genomics Consortium

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Abstract

BACKGROUND: Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes.

METHODS: Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations.

RESULTS: Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex.

CONCLUSIONS: Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.

Originalsprog	Engelsk
Tidsskrift	Psychological Medicine
Vol/bind	53
Nummer	6
Sider (fra-til)	2619-2633
Antal sider	15
ISSN	0033-2917
DOI	https://doi.org/10.1017/S0033291721004554
Status	Udgivet - 2023

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10.1017/S0033291721004554Licens: CC BY

mapping-anorexia-nervosa-genes-to-clinical-phenotypesForlagets udgivne version, 954 KBLicens: CC BY

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Johnson, J. S., Cote, A. C., Dobbyn, A., Sloofman, L. G., Xu, J., Cotter, L., Charney, A. W., Birgegård, A., Jordan, J., Kennedy, M., Landén, M., Maguire, S. L., Martin, N. G., Mortensen, P. B., Thornton, L. M., Bulik, C. M., Huckins, L. M., & Eating Disorders Working Group of the Psychiatric Genomics Consortium (2023). Mapping anorexia nervosa genes to clinical phenotypes. Psychological Medicine, 53(6), 2619-2633. https://doi.org/10.1017/S0033291721004554

@article{9217c7a5e24b4508b71dc68be673d49c,

title = "Mapping anorexia nervosa genes to clinical phenotypes",

abstract = "BACKGROUND: Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes.METHODS: Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe{\texttrademark} Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations.RESULTS: Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex.CONCLUSIONS: Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.",

keywords = "Anorexia nervosa, EHR, PrediXcan, pheWAS, transcriptomic imputation",

author = "Johnson, {Jessica S} and Cote, {Alanna C} and Amanda Dobbyn and Sloofman, {Laura G} and Jiayi Xu and Liam Cotter and Charney, {Alexander W} and Andreas Birgeg{\aa}rd and Jennifer Jordan and Martin Kennedy and Mika{\'e}l Land{\'e}n and Maguire, {Sarah L} and Martin, {Nicholas G} and Mortensen, {Preben Bo} and Thornton, {Laura M} and Bulik, {Cynthia M} and Huckins, {Laura M} and {Eating Disorders Working Group of the Psychiatric Genomics Consortium}",

year = "2023",

doi = "10.1017/S0033291721004554",

language = "English",

volume = "53",

pages = "2619--2633",

journal = "Psychological Medicine",

issn = "0033-2917",

publisher = "Cambridge University Press",

number = "6",

}

Johnson, JS, Cote, AC, Dobbyn, A, Sloofman, LG, Xu, J, Cotter, L, Charney, AW, Birgegård, A, Jordan, J, Kennedy, M, Landén, M, Maguire, SL, Martin, NG, Mortensen, PB, Thornton, LM, Bulik, CM, Huckins, LM & Eating Disorders Working Group of the Psychiatric Genomics Consortium 2023, 'Mapping anorexia nervosa genes to clinical phenotypes', Psychological Medicine, bind 53, nr. 6, s. 2619-2633. https://doi.org/10.1017/S0033291721004554

TY - JOUR

T1 - Mapping anorexia nervosa genes to clinical phenotypes

AU - Johnson, Jessica S

AU - Cote, Alanna C

AU - Dobbyn, Amanda

AU - Sloofman, Laura G

AU - Xu, Jiayi

AU - Cotter, Liam

AU - Charney, Alexander W

AU - Birgegård, Andreas

AU - Jordan, Jennifer

AU - Kennedy, Martin

AU - Landén, Mikaél

AU - Maguire, Sarah L

AU - Martin, Nicholas G

AU - Mortensen, Preben Bo

AU - Thornton, Laura M

AU - Bulik, Cynthia M

AU - Huckins, Laura M

AU - Eating Disorders Working Group of the Psychiatric Genomics Consortium

PY - 2023

Y1 - 2023

N2 - BACKGROUND: Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes.METHODS: Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations.RESULTS: Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex.CONCLUSIONS: Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.

AB - BACKGROUND: Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes.METHODS: Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations.RESULTS: Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex.CONCLUSIONS: Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.

KW - Anorexia nervosa

KW - EHR

KW - PrediXcan

KW - pheWAS

KW - transcriptomic imputation

UR - http://www.scopus.com/inward/record.url?scp=85128406545&partnerID=8YFLogxK

U2 - 10.1017/S0033291721004554

DO - 10.1017/S0033291721004554

M3 - Journal article

C2 - 35379376

SN - 0033-2917

VL - 53

SP - 2619

EP - 2633

JO - Psychological Medicine

JF - Psychological Medicine

IS - 6

ER -

Mapping anorexia nervosa genes to clinical phenotypes

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