An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos

Chris R Gignoux; Dara G Torgerson; Maria Pino-Yanes; Lawrence H Uricchio; Joshua Galanter; Lindsey A Roth; Celeste Eng; Donglei Hu; Elizabeth A Nguyen; Scott Huntsman; Rasika A Mathias; Rajesh Kumar; Jose Rodriguez-Santana; Neeta Thakur; Sam S Oh; Meghan McGarry; Andres Moreno-Estrada; Karla Sandoval; Cheryl A Winkler; Max A Seibold; Badri Padhukasahasram; David V Conti; Harold J Farber; Pedro Avila; Emerita Brigino-Buenaventura; Michael Lenoir; Kelley Meade; Denise Serebrisky; Luisa N Borrell; William Rodriguez-Cintron; Shannon Thyne; Bonnie R Joubert; Isabelle Romieu; Albert M Levin; Juan-Jose Sienra-Monge; Blanca Estela Del Rio-Navarro; Weiniu Gan; Benjamin A Raby; Scott T Weiss; Eugene Bleecker; Deborah A Meyers; Fernando J Martinez; W James Gauderman; Frank Gilliland; Stephanie J London; Carlos D Bustamante; Dan L Nicolae; Carole Ober; Saunak Sen; Kathleen Barnes

doi:10.1016/j.jaci.2016.08.057

An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos

Chris R Gignoux, Dara G Torgerson, Maria Pino-Yanes, Lawrence H Uricchio, Joshua Galanter, Lindsey A Roth, Celeste Eng, Donglei Hu, Elizabeth A Nguyen, Scott Huntsman, Rasika A Mathias, Rajesh Kumar, Jose Rodriguez-Santana, Neeta Thakur, Sam S Oh, Meghan McGarry, Andres Moreno-Estrada, Karla Sandoval, Cheryl A Winkler, Max A SeiboldBadri Padhukasahasram, David V Conti, Harold J Farber, Pedro Avila, Emerita Brigino-Buenaventura, Michael Lenoir, Kelley Meade, Denise Serebrisky, Luisa N Borrell, William Rodriguez-Cintron, Shannon Thyne, Bonnie R Joubert, Isabelle Romieu, Albert M Levin, Juan-Jose Sienra-Monge, Blanca Estela Del Rio-Navarro, Weiniu Gan, Benjamin A Raby, Scott T Weiss, Eugene Bleecker, Deborah A Meyers, Fernando J Martinez, W James Gauderman, Frank Gilliland, Stephanie J London, Carlos D Bustamante, Dan L Nicolae, Carole Ober, Saunak Sen, Kathleen Barnes

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies.

OBJECTIVE: Perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility.

METHODS: We leveraged the mixed ancestry of 3,902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3,774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of >500 individuals from 3 racial/ethnic groups.

RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (p=6.8x10-6), where Native American ancestry was associated with increased risk of asthma (OR=1.20, 95% CI=1.07-1.34, p=0.002) and European ancestry with protection (OR=0.86, 95% CI=0.77-0.96, p=0.008). Our findings replicated in an independent childhood asthma study in Latinos (p=5.3x10-3, combined p=2.6x10-7). Fine mapping of 18q21 in 1,978 Latinos identified a significant association with multiple variants 5' of SMAD2 in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression, OR=3.93, 95% CI 2.12-7.28,p<0.001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma.

CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos, and implicated multiple ancestry-informative non-coding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

Original language	English (US)
Journal	The Journal of Allergy and Clinical Immunology
DOIs	https://doi.org/10.1016/j.jaci.2016.08.057
State	E-pub ahead of print - Sep 7 2018

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Gignoux, C. R., Torgerson, D. G., Pino-Yanes, M., Uricchio, L. H., Galanter, J., Roth, L. A., Eng, C., Hu, D., Nguyen, E. A., Huntsman, S., Mathias, R. A., Kumar, R., Rodriguez-Santana, J., Thakur, N., Oh, S. S., McGarry, M., Moreno-Estrada, A., Sandoval, K., Winkler, C. A., ... Barnes, K. (2018). An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos. The Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2016.08.057

Gignoux, Chris R ; Torgerson, Dara G ; Pino-Yanes, Maria ; Uricchio, Lawrence H ; Galanter, Joshua ; Roth, Lindsey A ; Eng, Celeste ; Hu, Donglei ; Nguyen, Elizabeth A ; Huntsman, Scott ; Mathias, Rasika A ; Kumar, Rajesh ; Rodriguez-Santana, Jose ; Thakur, Neeta ; Oh, Sam S ; McGarry, Meghan ; Moreno-Estrada, Andres ; Sandoval, Karla ; Winkler, Cheryl A ; Seibold, Max A ; Padhukasahasram, Badri ; Conti, David V ; Farber, Harold J ; Avila, Pedro ; Brigino-Buenaventura, Emerita ; Lenoir, Michael ; Meade, Kelley ; Serebrisky, Denise ; Borrell, Luisa N ; Rodriguez-Cintron, William ; Thyne, Shannon ; Joubert, Bonnie R ; Romieu, Isabelle ; Levin, Albert M ; Sienra-Monge, Juan-Jose ; Del Rio-Navarro, Blanca Estela ; Gan, Weiniu ; Raby, Benjamin A ; Weiss, Scott T ; Bleecker, Eugene ; Meyers, Deborah A ; Martinez, Fernando J ; Gauderman, W James ; Gilliland, Frank ; London, Stephanie J ; Bustamante, Carlos D ; Nicolae, Dan L ; Ober, Carole ; Sen, Saunak ; Barnes, Kathleen. / An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos. In: The Journal of Allergy and Clinical Immunology. 2018.

@article{bb65458ba6ce4b25a07119d63c184b5c,

title = "An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos",

abstract = "BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies.OBJECTIVE: Perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility.METHODS: We leveraged the mixed ancestry of 3,902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3,774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of >500 individuals from 3 racial/ethnic groups.RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (p=6.8x10-6), where Native American ancestry was associated with increased risk of asthma (OR=1.20, 95% CI=1.07-1.34, p=0.002) and European ancestry with protection (OR=0.86, 95% CI=0.77-0.96, p=0.008). Our findings replicated in an independent childhood asthma study in Latinos (p=5.3x10-3, combined p=2.6x10-7). Fine mapping of 18q21 in 1,978 Latinos identified a significant association with multiple variants 5' of SMAD2 in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression, OR=3.93, 95% CI 2.12-7.28,p<0.001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma.CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos, and implicated multiple ancestry-informative non-coding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.",

author = "Gignoux, {Chris R} and Torgerson, {Dara G} and Maria Pino-Yanes and Uricchio, {Lawrence H} and Joshua Galanter and Roth, {Lindsey A} and Celeste Eng and Donglei Hu and Nguyen, {Elizabeth A} and Scott Huntsman and Mathias, {Rasika A} and Rajesh Kumar and Jose Rodriguez-Santana and Neeta Thakur and Oh, {Sam S} and Meghan McGarry and Andres Moreno-Estrada and Karla Sandoval and Winkler, {Cheryl A} and Seibold, {Max A} and Badri Padhukasahasram and Conti, {David V} and Farber, {Harold J} and Pedro Avila and Emerita Brigino-Buenaventura and Michael Lenoir and Kelley Meade and Denise Serebrisky and Borrell, {Luisa N} and William Rodriguez-Cintron and Shannon Thyne and Joubert, {Bonnie R} and Isabelle Romieu and Levin, {Albert M} and Juan-Jose Sienra-Monge and {Del Rio-Navarro}, {Blanca Estela} and Weiniu Gan and Raby, {Benjamin A} and Weiss, {Scott T} and Eugene Bleecker and Meyers, {Deborah A} and Martinez, {Fernando J} and Gauderman, {W James} and Frank Gilliland and London, {Stephanie J} and Bustamante, {Carlos D} and Nicolae, {Dan L} and Carole Ober and Saunak Sen and Kathleen Barnes",

note = "Copyright {\textcopyright} 2018. Published by Elsevier Inc.",

year = "2018",

month = sep,

day = "7",

doi = "10.1016/j.jaci.2016.08.057",

language = "English (US)",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

}

Gignoux, CR, Torgerson, DG, Pino-Yanes, M, Uricchio, LH, Galanter, J, Roth, LA, Eng, C, Hu, D, Nguyen, EA, Huntsman, S, Mathias, RA, Kumar, R, Rodriguez-Santana, J, Thakur, N, Oh, SS, McGarry, M, Moreno-Estrada, A, Sandoval, K, Winkler, CA, Seibold, MA, Padhukasahasram, B, Conti, DV, Farber, HJ, Avila, P, Brigino-Buenaventura, E, Lenoir, M, Meade, K, Serebrisky, D, Borrell, LN, Rodriguez-Cintron, W, Thyne, S, Joubert, BR, Romieu, I, Levin, AM, Sienra-Monge, J-J, Del Rio-Navarro, BE, Gan, W, Raby, BA, Weiss, ST, Bleecker, E, Meyers, DA, Martinez, FJ, Gauderman, WJ, Gilliland, F, London, SJ, Bustamante, CD, Nicolae, DL, Ober, C, Sen, S & Barnes, K 2018, 'An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos', The Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2016.08.057

An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos. / Gignoux, Chris R; Torgerson, Dara G; Pino-Yanes, Maria; Uricchio, Lawrence H; Galanter, Joshua; Roth, Lindsey A; Eng, Celeste; Hu, Donglei; Nguyen, Elizabeth A; Huntsman, Scott; Mathias, Rasika A; Kumar, Rajesh; Rodriguez-Santana, Jose; Thakur, Neeta; Oh, Sam S; McGarry, Meghan; Moreno-Estrada, Andres; Sandoval, Karla; Winkler, Cheryl A; Seibold, Max A; Padhukasahasram, Badri; Conti, David V; Farber, Harold J; Avila, Pedro; Brigino-Buenaventura, Emerita; Lenoir, Michael; Meade, Kelley; Serebrisky, Denise; Borrell, Luisa N; Rodriguez-Cintron, William; Thyne, Shannon; Joubert, Bonnie R; Romieu, Isabelle; Levin, Albert M; Sienra-Monge, Juan-Jose; Del Rio-Navarro, Blanca Estela; Gan, Weiniu; Raby, Benjamin A; Weiss, Scott T; Bleecker, Eugene; Meyers, Deborah A; Martinez, Fernando J; Gauderman, W James; Gilliland, Frank; London, Stephanie J; Bustamante, Carlos D; Nicolae, Dan L; Ober, Carole; Sen, Saunak; Barnes, Kathleen.

In: The Journal of Allergy and Clinical Immunology, 07.09.2018.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos

AU - Gignoux, Chris R

AU - Torgerson, Dara G

AU - Pino-Yanes, Maria

AU - Uricchio, Lawrence H

AU - Galanter, Joshua

AU - Roth, Lindsey A

AU - Eng, Celeste

AU - Hu, Donglei

AU - Nguyen, Elizabeth A

AU - Huntsman, Scott

AU - Mathias, Rasika A

AU - Kumar, Rajesh

AU - Rodriguez-Santana, Jose

AU - Thakur, Neeta

AU - Oh, Sam S

AU - McGarry, Meghan

AU - Moreno-Estrada, Andres

AU - Sandoval, Karla

AU - Winkler, Cheryl A

AU - Seibold, Max A

AU - Padhukasahasram, Badri

AU - Conti, David V

AU - Farber, Harold J

AU - Avila, Pedro

AU - Brigino-Buenaventura, Emerita

AU - Lenoir, Michael

AU - Meade, Kelley

AU - Serebrisky, Denise

AU - Borrell, Luisa N

AU - Rodriguez-Cintron, William

AU - Thyne, Shannon

AU - Joubert, Bonnie R

AU - Romieu, Isabelle

AU - Levin, Albert M

AU - Sienra-Monge, Juan-Jose

AU - Del Rio-Navarro, Blanca Estela

AU - Gan, Weiniu

AU - Raby, Benjamin A

AU - Weiss, Scott T

AU - Bleecker, Eugene

AU - Meyers, Deborah A

AU - Martinez, Fernando J

AU - Gauderman, W James

AU - Gilliland, Frank

AU - London, Stephanie J

AU - Bustamante, Carlos D

AU - Nicolae, Dan L

AU - Ober, Carole

AU - Sen, Saunak

AU - Barnes, Kathleen

PY - 2018/9/7

Y1 - 2018/9/7

N2 - BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies.OBJECTIVE: Perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility.METHODS: We leveraged the mixed ancestry of 3,902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3,774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of >500 individuals from 3 racial/ethnic groups.RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (p=6.8x10-6), where Native American ancestry was associated with increased risk of asthma (OR=1.20, 95% CI=1.07-1.34, p=0.002) and European ancestry with protection (OR=0.86, 95% CI=0.77-0.96, p=0.008). Our findings replicated in an independent childhood asthma study in Latinos (p=5.3x10-3, combined p=2.6x10-7). Fine mapping of 18q21 in 1,978 Latinos identified a significant association with multiple variants 5' of SMAD2 in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression, OR=3.93, 95% CI 2.12-7.28,p<0.001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma.CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos, and implicated multiple ancestry-informative non-coding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

AB - BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies.OBJECTIVE: Perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility.METHODS: We leveraged the mixed ancestry of 3,902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3,774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of >500 individuals from 3 racial/ethnic groups.RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (p=6.8x10-6), where Native American ancestry was associated with increased risk of asthma (OR=1.20, 95% CI=1.07-1.34, p=0.002) and European ancestry with protection (OR=0.86, 95% CI=0.77-0.96, p=0.008). Our findings replicated in an independent childhood asthma study in Latinos (p=5.3x10-3, combined p=2.6x10-7). Fine mapping of 18q21 in 1,978 Latinos identified a significant association with multiple variants 5' of SMAD2 in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression, OR=3.93, 95% CI 2.12-7.28,p<0.001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma.CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos, and implicated multiple ancestry-informative non-coding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

U2 - 10.1016/j.jaci.2016.08.057

DO - 10.1016/j.jaci.2016.08.057

M3 - Article

C2 - 30201514

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

ER -