Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways

A. S. Howe; Henriette N Buttenschön; A. Bani-Fatemi; E Maron; T Otowa; A Erhardt; Elisabeth B. Binder; N. O. Gregersen; O Mors; D. P. Woldbye; K Domschke; A Reif; J. Shlik; S. Kks; Y Kawamura; A. Miyashita; R. Kuwano; K Tokunaga; H. Tanii; J. W. Smoller; T. Sasaki; D. Koszycki; Vincenzo De Luca

doi:10.1038/mp.2015.138

Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways

A. S. Howe^*, Henriette N Buttenschön, A. Bani-Fatemi, E Maron, T Otowa, A Erhardt, Elisabeth B. Binder, N. O. Gregersen, O Mors, D. P. Woldbye, K Domschke, A Reif, J. Shlik, S. Kks, Y Kawamura, A. Miyashita, R. Kuwano, K Tokunaga, H. Tanii, J. W. SmollerT. Sasaki, D. Koszycki, Vincenzo De Luca

^*Corresponding author for this work

47 Citations (Scopus)

Abstract

The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed for three variants, TMEM132D rs7370927 (T allele: odds ratio (OR)=1.27, 95% confidence interval (CI): 1.15-1.40, P=2.49 × 10 -6), rs11060369 (CC genotype: OR=0.65, 95% CI: 0.53-0.79, P=1.81 × 10 -5) and COMT rs4680 (Val (G) allele: OR=1.27, 95% CI: 1.14-1.42, P=2.49 × 10 -5) in studies with samples of European ancestry. Nominal associations that did not survive correction for multiple testing were observed for NPSR1 rs324891 (T allele: OR=1.22, 95% CI: 1.07-1.38, P=0.002), TPH1 rs1800532 (AA genotype: OR=1.46, 95% CI: 1.14-1.89, P=0.003) and HTR2A rs6313 (T allele: OR=1.19, 95% CI: 1.07-1.33, P=0.002) in studies with samples of European ancestry and for MAOA-uVNTR in female PD (low-active alleles: OR=1.21, 95% CI: 1.07-1.38, P=0.004). No significant associations were observed in the secondary analyses considering sex, agoraphobia co-morbidity and studies with samples of Asian ancestry. Although these findings highlight a few associations, PD likely involves genetic variation in a multitude of biological pathways that is diverse among populations. Future studies must incorporate larger sample sizes and genome-wide approaches to further quantify the observed genetic variation among populations and subphenotypes of PD.

Original language	English
Journal	Molecular Psychiatry
Volume	21
Issue number	5
Pages (from-to)	665-679
Number of pages	15
ISSN	1359-4184
DOIs	https://doi.org/10.1038/mp.2015.138
Publication status	Published - 2016

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Howe, A. S., Buttenschön, H. N., Bani-Fatemi, A., Maron, E., Otowa, T., Erhardt, A., Binder, E. B., Gregersen, N. O., Mors, O., Woldbye, D. P., Domschke, K., Reif, A., Shlik, J., Kks, S., Kawamura, Y., Miyashita, A., Kuwano, R., Tokunaga, K., Tanii, H., ... De Luca, V. (2016). Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways. Molecular Psychiatry, 21(5), 665-679. https://doi.org/10.1038/mp.2015.138

Howe, AS, Buttenschön, HN, Bani-Fatemi, A, Maron, E, Otowa, T, Erhardt, A, Binder, EB, Gregersen, NO, Mors, O, Woldbye, DP, Domschke, K, Reif, A, Shlik, J, Kks, S, Kawamura, Y, Miyashita, A, Kuwano, R, Tokunaga, K, Tanii, H, Smoller, JW, Sasaki, T, Koszycki, D & De Luca, V 2016, 'Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways', Molecular Psychiatry, vol. 21, no. 5, pp. 665-679. https://doi.org/10.1038/mp.2015.138

@article{db3636edf4764367b30a2e50adeffb97,

title = "Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways",

abstract = "The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed for three variants, TMEM132D rs7370927 (T allele: odds ratio (OR)=1.27, 95% confidence interval (CI): 1.15-1.40, P=2.49 × 10 -6), rs11060369 (CC genotype: OR=0.65, 95% CI: 0.53-0.79, P=1.81 × 10 -5) and COMT rs4680 (Val (G) allele: OR=1.27, 95% CI: 1.14-1.42, P=2.49 × 10 -5) in studies with samples of European ancestry. Nominal associations that did not survive correction for multiple testing were observed for NPSR1 rs324891 (T allele: OR=1.22, 95% CI: 1.07-1.38, P=0.002), TPH1 rs1800532 (AA genotype: OR=1.46, 95% CI: 1.14-1.89, P=0.003) and HTR2A rs6313 (T allele: OR=1.19, 95% CI: 1.07-1.33, P=0.002) in studies with samples of European ancestry and for MAOA-uVNTR in female PD (low-active alleles: OR=1.21, 95% CI: 1.07-1.38, P=0.004). No significant associations were observed in the secondary analyses considering sex, agoraphobia co-morbidity and studies with samples of Asian ancestry. Although these findings highlight a few associations, PD likely involves genetic variation in a multitude of biological pathways that is diverse among populations. Future studies must incorporate larger sample sizes and genome-wide approaches to further quantify the observed genetic variation among populations and subphenotypes of PD.",

author = "Howe, {A. S.} and Buttensch{\"o}n, {Henriette N} and A. Bani-Fatemi and E Maron and T Otowa and A Erhardt and Binder, {Elisabeth B.} and Gregersen, {N. O.} and O Mors and Woldbye, {D. P.} and K Domschke and A Reif and J. Shlik and S. Kks and Y Kawamura and A. Miyashita and R. Kuwano and K Tokunaga and H. Tanii and Smoller, {J. W.} and T. Sasaki and D. Koszycki and {De Luca}, Vincenzo",

year = "2016",

doi = "10.1038/mp.2015.138",

language = "English",

volume = "21",

pages = "665--679",

journal = "Molecular Psychiatry",

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T1 - Candidate genes in panic disorder

T2 - meta-analyses of 23 common variants in major anxiogenic pathways

AU - Howe, A. S.

AU - Buttenschön, Henriette N

AU - Bani-Fatemi, A.

AU - Maron, E

AU - Otowa, T

AU - Erhardt, A

AU - Binder, Elisabeth B.

AU - Gregersen, N. O.

AU - Mors, O

AU - Woldbye, D. P.

AU - Domschke, K

AU - Reif, A

AU - Shlik, J.

AU - Kks, S.

AU - Kawamura, Y

AU - Miyashita, A.

AU - Kuwano, R.

AU - Tokunaga, K

AU - Tanii, H.

AU - Smoller, J. W.

AU - Sasaki, T.

AU - Koszycki, D.

AU - De Luca, Vincenzo

PY - 2016

Y1 - 2016

N2 - The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed for three variants, TMEM132D rs7370927 (T allele: odds ratio (OR)=1.27, 95% confidence interval (CI): 1.15-1.40, P=2.49 × 10 -6), rs11060369 (CC genotype: OR=0.65, 95% CI: 0.53-0.79, P=1.81 × 10 -5) and COMT rs4680 (Val (G) allele: OR=1.27, 95% CI: 1.14-1.42, P=2.49 × 10 -5) in studies with samples of European ancestry. Nominal associations that did not survive correction for multiple testing were observed for NPSR1 rs324891 (T allele: OR=1.22, 95% CI: 1.07-1.38, P=0.002), TPH1 rs1800532 (AA genotype: OR=1.46, 95% CI: 1.14-1.89, P=0.003) and HTR2A rs6313 (T allele: OR=1.19, 95% CI: 1.07-1.33, P=0.002) in studies with samples of European ancestry and for MAOA-uVNTR in female PD (low-active alleles: OR=1.21, 95% CI: 1.07-1.38, P=0.004). No significant associations were observed in the secondary analyses considering sex, agoraphobia co-morbidity and studies with samples of Asian ancestry. Although these findings highlight a few associations, PD likely involves genetic variation in a multitude of biological pathways that is diverse among populations. Future studies must incorporate larger sample sizes and genome-wide approaches to further quantify the observed genetic variation among populations and subphenotypes of PD.

AB - The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed for three variants, TMEM132D rs7370927 (T allele: odds ratio (OR)=1.27, 95% confidence interval (CI): 1.15-1.40, P=2.49 × 10 -6), rs11060369 (CC genotype: OR=0.65, 95% CI: 0.53-0.79, P=1.81 × 10 -5) and COMT rs4680 (Val (G) allele: OR=1.27, 95% CI: 1.14-1.42, P=2.49 × 10 -5) in studies with samples of European ancestry. Nominal associations that did not survive correction for multiple testing were observed for NPSR1 rs324891 (T allele: OR=1.22, 95% CI: 1.07-1.38, P=0.002), TPH1 rs1800532 (AA genotype: OR=1.46, 95% CI: 1.14-1.89, P=0.003) and HTR2A rs6313 (T allele: OR=1.19, 95% CI: 1.07-1.33, P=0.002) in studies with samples of European ancestry and for MAOA-uVNTR in female PD (low-active alleles: OR=1.21, 95% CI: 1.07-1.38, P=0.004). No significant associations were observed in the secondary analyses considering sex, agoraphobia co-morbidity and studies with samples of Asian ancestry. Although these findings highlight a few associations, PD likely involves genetic variation in a multitude of biological pathways that is diverse among populations. Future studies must incorporate larger sample sizes and genome-wide approaches to further quantify the observed genetic variation among populations and subphenotypes of PD.

U2 - 10.1038/mp.2015.138

DO - 10.1038/mp.2015.138

M3 - Journal article

C2 - 26390831

AN - SCOPUS:84941888802

SN - 1359-4184

VL - 21

SP - 665

EP - 679

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 5

ER -

Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways

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