Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

Andries T Marees; Anke R Hammerschlag; Lisa Bastarache; Hilde de Kluiver; Florence Vorspan; Wim van den Brink; Dirk J Smit; Damiaan Denys; Eric R Gamazon; Ruifang Li-Gao; Elemi J Breetvelt; Mark C H de Groot; Tessel E Galesloot; Sita H Vermeulen; Jan L Poppelaars; Patrick C Souverein; Renske Keeman; Renée de Mutsert; Raymond Noordam; Frits R Rosendaal; Najada Stringa; Dennis O Mook-Kanamori; Ilonca Vaartjes; Lambertus A Kiemeney; Martin den Heijer; Natasja M van Schoor; Olaf H Klungel; Anke H Maitland-Van der Zee; Marjanka K Schmidt; Tinca J C Polderman; Andries R van der Leij; Danielle Posthuma; Eske M Derks

doi:10.1016/j.drugalcdep.2018.03.026

Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

Andries T Marees, Anke R Hammerschlag, Lisa Bastarache, Hilde de Kluiver, Florence Vorspan, Wim van den Brink, Dirk J Smit, Damiaan Denys, Eric R Gamazon, Ruifang Li-Gao, Elemi J Breetvelt, Mark C H de Groot, Tessel E Galesloot, Sita H Vermeulen, Jan L Poppelaars, Patrick C Souverein, Renske Keeman, Renée de Mutsert, Raymond Noordam, Frits R RosendaalNajada Stringa, Dennis O Mook-Kanamori, Ilonca Vaartjes, Lambertus A Kiemeney, Martin den Heijer, Natasja M van Schoor, Olaf H Klungel, Anke H Maitland-Van der Zee, Marjanka K Schmidt, Tinca J C Polderman, Andries R van der Leij, Danielle Posthuma, Eske M Derks

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Abstract

BACKGROUND: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use.

METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses.

RESULTS: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10-7) and rs8034191 (p = 6.31 × 10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use.

DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.

Original language	English
Pages (from-to)	94-101
Number of pages	8
Journal	Drug and Alcohol Dependence
Volume	188
DOIs	https://doi.org/10.1016/j.drugalcdep.2018.03.026
Publication status	Published - 1 Jul 2018

Keywords

Addiction
Exome
Rare variants
Tobacco
Nicotine
Alcohol
PRS
Pathway analysis

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10.1016/j.drugalcdep.2018.03.026

1-s2.0-S0376871618302266-mainFinal published version, 539 KBLicence: CC BY-NC-ND

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Marees, A. T., Hammerschlag, A. R., Bastarache, L., de Kluiver, H., Vorspan, F., van den Brink, W., Smit, D. J., Denys, D., Gamazon, E. R., Li-Gao, R., Breetvelt, E. J., de Groot, M. C. H., Galesloot, T. E., Vermeulen, S. H., Poppelaars, J. L., Souverein, P. C., Keeman, R., de Mutsert, R., Noordam, R., ... Derks, E. M. (2018). Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use. Drug and Alcohol Dependence, 188, 94-101. https://doi.org/10.1016/j.drugalcdep.2018.03.026

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title = "Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use",

abstract = "BACKGROUND: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use.METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of {"}alcoholism{"} (N = 25,508) and {"}tobacco use disorder{"} (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses.RESULTS: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10-7) and rs8034191 (p = 6.31 × 10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use.DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.",

keywords = "Addiction, Exome, Rare variants, Tobacco, Nicotine, Alcohol, PRS, Pathway analysis",

author = "Marees, {Andries T} and Hammerschlag, {Anke R} and Lisa Bastarache and {de Kluiver}, Hilde and Florence Vorspan and {van den Brink}, Wim and Smit, {Dirk J} and Damiaan Denys and Gamazon, {Eric R} and Ruifang Li-Gao and Breetvelt, {Elemi J} and {de Groot}, {Mark C H} and Galesloot, {Tessel E} and Vermeulen, {Sita H} and Poppelaars, {Jan L} and Souverein, {Patrick C} and Renske Keeman and {de Mutsert}, Ren{\'e}e and Raymond Noordam and Rosendaal, {Frits R} and Najada Stringa and Mook-Kanamori, {Dennis O} and Ilonca Vaartjes and Kiemeney, {Lambertus A} and {den Heijer}, Martin and {van Schoor}, {Natasja M} and Klungel, {Olaf H} and {Maitland-Van der Zee}, {Anke H} and Schmidt, {Marjanka K} and Polderman, {Tinca J C} and {van der Leij}, {Andries R} and Danielle Posthuma and Derks, {Eske M}",

year = "2018",

month = jul,

day = "1",

doi = "10.1016/j.drugalcdep.2018.03.026",

language = "English",

volume = "188",

pages = "94--101",

journal = "Drug and Alcohol Dependence",

issn = "0376-8716",

publisher = "Elsevier Ireland Ltd.",

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Marees, AT, Hammerschlag, AR, Bastarache, L, de Kluiver, H, Vorspan, F, van den Brink, W, Smit, DJ, Denys, D, Gamazon, ER, Li-Gao, R, Breetvelt, EJ, de Groot, MCH, Galesloot, TE, Vermeulen, SH, Poppelaars, JL, Souverein, PC, Keeman, R, de Mutsert, R, Noordam, R, Rosendaal, FR, Stringa, N, Mook-Kanamori, DO, Vaartjes, I, Kiemeney, LA, den Heijer, M, van Schoor, NM, Klungel, OH, Maitland-Van der Zee, AH, Schmidt, MK, Polderman, TJC, van der Leij, AR, Posthuma, D & Derks, EM 2018, 'Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use', Drug and Alcohol Dependence, vol. 188, pp. 94-101. https://doi.org/10.1016/j.drugalcdep.2018.03.026

TY - JOUR

T1 - Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

AU - Marees, Andries T

AU - Hammerschlag, Anke R

AU - Bastarache, Lisa

AU - de Kluiver, Hilde

AU - Vorspan, Florence

AU - van den Brink, Wim

AU - Smit, Dirk J

AU - Denys, Damiaan

AU - Gamazon, Eric R

AU - Li-Gao, Ruifang

AU - Breetvelt, Elemi J

AU - de Groot, Mark C H

AU - Galesloot, Tessel E

AU - Vermeulen, Sita H

AU - Poppelaars, Jan L

AU - Souverein, Patrick C

AU - Keeman, Renske

AU - de Mutsert, Renée

AU - Noordam, Raymond

AU - Rosendaal, Frits R

AU - Stringa, Najada

AU - Mook-Kanamori, Dennis O

AU - Vaartjes, Ilonca

AU - Kiemeney, Lambertus A

AU - den Heijer, Martin

AU - van Schoor, Natasja M

AU - Klungel, Olaf H

AU - Maitland-Van der Zee, Anke H

AU - Schmidt, Marjanka K

AU - Polderman, Tinca J C

AU - van der Leij, Andries R

AU - Posthuma, Danielle

AU - Derks, Eske M

PY - 2018/7/1

Y1 - 2018/7/1

N2 - BACKGROUND: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use.METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses.RESULTS: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10-7) and rs8034191 (p = 6.31 × 10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use.DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.

AB - BACKGROUND: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use.METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses.RESULTS: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10-7) and rs8034191 (p = 6.31 × 10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use.DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.

KW - Addiction

KW - Exome

KW - Rare variants

KW - Tobacco

KW - Nicotine

KW - Alcohol

KW - PRS

KW - Pathway analysis

U2 - 10.1016/j.drugalcdep.2018.03.026

DO - 10.1016/j.drugalcdep.2018.03.026

M3 - Article

C2 - 29758381

SN - 0376-8716

VL - 188

SP - 94

EP - 101

JO - Drug and Alcohol Dependence

JF - Drug and Alcohol Dependence

ER -

Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

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Keywords

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