Genetic Polymorphisms and Generalized Anxiety Disorder: a systematic review

Alves, Verônica de Medeiros; Moura, Edilson Leite de; Correia, Larissa Tenório Andrade; Nardi, Antonio E.

doi:10.5935/MedicalExpress.2017.01.01

Brasil

Español English

REVIEW • MedicalExpress (São Paulo, online) 4 (1) • Jan-Feb 2017 • https://doi.org/10.5935/MedicalExpress.2017.01.01 copy

Genetic Polymorphisms and Generalized Anxiety Disorder: a systematic review

POLIMORFISMOS GENÉTICOS E TRANSTORNOS GENERALIZADOS DE ANSIEDADE

Authorship SCIMAGO INSTITUTIONS RANKINGS

OBJECTIVE:

Generalized Anxiety Disorder is a disease characterized by feelings of anxiety, fear, excessive worrying and tension in the face of life experiences. This study aims to identify genetic polymorphisms associated with Generalized Anxiety Disorder described in scientific literature.

METHOD:

This review was set up by searching PubMed/Medline, Web of Science and Scopus database using the following key words: "gene and generalized anxiety disorder", "SNP and generalized anxiety disorder" and "polymorphism and generalized anxiety disorder".

RESULTS:

We found ten polymorphic varieties of nine genes that showed association and seven polymorphic varieties of three genes that showed no association with Generalized Anxiety disorder: genes NPY, BDNF, BLC2, DED2, RGS2, HTR1A, MAOA, ERS2 and 5-HTT showed association, whereas BDNF, ERS1 and TPH showed no association with the Disorder. Conflicting results regarding BDNF come from different studies.

CONCLUSION:

This review identified a variety of genetic polymorphisms, that have been studied in relation to Generalized Anxiety Disorder. Taken jointly, their results are inconclusive, showing that more genetic studies focused on this mental disorder are necessary.

KEYWORDS:
Polymorphisms; Generalized anxiety disorder; Gene

Reference	Candidate gene	Polymorphism	Sample, N	Country	Age	Genotyping method	Results
Amstadter et al, 2010 ¹⁹19 Amstadter AB, Koenen KC, Ruggiero KJ, Acierno R, Galea S, Kilpatrick DG, et al. NPY Moderates the Relation between Hurricane Exposure and Generalized Anxiety Disorder in an Epidemiologic Sample of Hurricane-Exposed Adults. Depress Anxiety. 2010;27(3):270-5. DOI: 10.1002/da.20648 https://doi.org/10.1002/da.20648...	NPY	Rs16147	Patients, 41 Controls, 575	USA (Florida)	Adults	TaqMan	Association with increased risk of GAD
Carlino et al, 2015 ²⁰20 Carlino D, Francavilla R, Baj G, Kulak K, d'Adamo P, Ulivi S, et al. Brain-derived neurotrophic factor serum levels in genetically isolated populations: gender-specifc association with anxiety disorder subtypes but not with anxiety levels or Val66Met polymorphism. peerJ. 2015;3:e1252. DOI: 10.7717/peerj.1252. https://doi.org/10.7717/peerj.1252...	BDNF	Val66Met (rs6265)	Patients, 91 Controls, 581	North-Eastern Italy	Adults	Illumina array	Association with GAD in females
Sipilä et al, 2010 ²¹21 Sipilä T, Kananen L, Greco D, Donner J, Silander K, Terwilliger JD, et al. An Association Analysis of Circadian Genes in Anxiety Disorders. Biol Psychiatry. 2010;67(12):1163-70. DOI: 10.1016/j.biopsych.2009.12.011 https://doi.org/10.1016/j.biopsych.2009....	BLC2 DRD2	Rs12454712 Rs4245146	Patients, 103 Controls, 206	Finland	Adults	Sequenom MassArray	Association with GAD. Association with GAD.
Koenen et al, 2009 ²2 Koenen KC, Amstadter AB, Ruggiero KJ, Acierno R, Galea S, Kilpatrick DG, et al. RGS2 and Generalized Anxiety Disorder in an Epidemiologic Sample of Hurricane-Exposed Adults. Depress Anxiety. 2009;26(4):309-15. DOI: 10.1002/da.20528 https://doi.org/10.1002/da.20528...	RGS2	Rs4606	Patients, 41 Controls, 566	USA (Florida)	Adults	TaqMan	Association with GAD.
Molina et al, 2011 ²²22 Molina E, Cervilla J, Rivera M, Torres F, Bellon JA, Moreno B, et al. Polymorphic variation at the serotonin 1-A receptor gene is associated with comorbid depression and generalized anxiety. Psychiatr Genet. 2011;21(4):195-201. DOI: 10.1097/YPG.0b013e3283457a48 https://doi.org/10.1097/YPG.0b013e328345...	HTR1A	C(-1019)G	Patients, 85 Controls, 974	Spain	Adults and Elderly	Sequenom MassArray	Association with comorbid MD and GAD.
Moreira et al, 2015 ⁴4 Moreira FP, Fabião JD, Bittencourt G, Wiener CD, Jansen K, Oses JP, et al. The Met allele of BDNF Val66Met polymorphism is associated with increased BDNF levels in generalized anxiety disorder. Psychiatric Genetics. 2015;25(5):201-7. DOI: 10.1097/YPG.0000000000000097 https://doi.org/10.1097/YPG.000000000000...	BDNF	Val66Met	Patients, 121 Controls, 695	Brazil	Adults	TaqMan	Met allele associated with increased BDNF in GAD.
Tadic et al, 2003 ²³23 Tadic A, Rujescu D, Szegedi A, Giegling I, Singer P, Möller HJ, et al. Association of a MAOA gene variant with generalized anxiety disorder, but not with panic disorder or major depression. Am J Med Genet B Neuropsychiatr Genet. 2003;117B(1):1-6. DOI: 10.1002/ajmg.b.10013 https://doi.org/10.1002/ajmg.b.10013...	MAOA	T941G	Patients, 34 Controls, 132	Germany	Adults	PCR-RFLP	941T allele is associated with GAD in females.
Ryan et al, 2011 ²⁴24 Ryan J, Scali J, Carrière I, Scarabin PY, Ritchie K, Ancelin ML. Estrogen receptor gene variants are associated with anxiety disorders in older women. Psychoneuroendocrinology. 2011;36(10):1582-6. DOI: 10.1016/j.psyneuen.2011.04.011 https://doi.org/10.1016/j.psyneuen.2011....	ESR2 ESR1	Rs1256049 Rs2234693 RS9340799 rs498693 rs1271572	Patients, 87 Controls, 850	France	Elderly	PCR SNP KASPar	The A allele is associated with an increased risk of GAD. No association. No association. No association. No association.
Wang et al, 2015 ²⁵25 Wang Y, Zhang H, Li Y, Wang Z, Fan Q, Yu S, et al. BDNF Val66Met polymorphism and plasma levels in Chinese Han population with obsessive-compulsive disorder and generalized anxiety disorder. J Affect Disord. 2015;186:7-12. DOI: 10.1016/j.jad.2015.07.023. https://doi.org/10.1016/j.jad.2015.07.02...	BDNF	Val66Met (rs6265)	Patients, 108 Controls, 99	China	Adults	TaqMan	No association.
You et al, 2005 ²⁶26 You JS, Hu SY, Chen B, Zhang HG. Serotonin transporter and tryptophan hydroxylase gene polymorphisms in Chinese patients with generalized anxiety disorder. Psychiatr Genet. 2005;15(1):7-11. DOI: 10.1097/00041444-200503000-00002 https://doi.org/10.1097/00041444-2005030...	5-HTT TPH	5-HTTLPR 5-HTT VNTR A218C	Patients, 138 Controls, 90	China	Adults	PCR conventional	SS genotype and S allele were associated with GAD. No association. No association.

REFERENCE	Candidate gene	Genotypes n (%)			p	Alleles n (%)		p
Molina et al ²²22 Molina E, Cervilla J, Rivera M, Torres F, Bellon JA, Moreno B, et al. Polymorphic variation at the serotonin 1-A receptor gene is associated with comorbid depression and generalized anxiety. Psychiatr Genet. 2011;21(4):195-201. DOI: 10.1097/YPG.0b013e3283457a48 https://doi.org/10.1097/YPG.0b013e328345...	BDNF Cases Controls	Val/Val 75 (62.0) 507 (72.9)	Val/Met 41 (33.9) 175 (25.2)	Met/Met 5 (4.1) 13 (1.9)	p 0.029	Val 0.79 0.85	Met 0.21 0.15	p 0.157
Tadic et al ²³23 Tadic A, Rujescu D, Szegedi A, Giegling I, Singer P, Möller HJ, et al. Association of a MAOA gene variant with generalized anxiety disorder, but not with panic disorder or major depression. Am J Med Genet B Neuropsychiatr Genet. 2003;117B(1):1-6. DOI: 10.1002/ajmg.b.10013 https://doi.org/10.1002/ajmg.b.10013...	MAOA Cases female Controls female	T 22 (64.7) 58 (43.9)	GT 10 (29.4) 54 (40.9)	GG 2 (5.9) 20 (15.2)	p 0.078	T 54 (79.4) 170 (64.4)	G 14 (20.6) 94 (35.6)	p 0.018
Ryan et al ²⁴24 Ryan J, Scali J, Carrière I, Scarabin PY, Ritchie K, Ancelin ML. Estrogen receptor gene variants are associated with anxiety disorders in older women. Psychoneuroendocrinology. 2011;36(10):1582-6. DOI: 10.1016/j.psyneuen.2011.04.011 https://doi.org/10.1016/j.psyneuen.2011.... *	ESR2 RS1256049 Cases	GG No values posted	GA No values posted	AA No values posted	p	G No values posted	A Author stated association, but posted no value	p 0.02
You et al ²⁶26 You JS, Hu SY, Chen B, Zhang HG. Serotonin transporter and tryptophan hydroxylase gene polymorphisms in Chinese patients with generalized anxiety disorder. Psychiatr Genet. 2005;15(1):7-11. DOI: 10.1097/00041444-200503000-00002 https://doi.org/10.1097/00041444-2005030...	5-HTT (5-HTTLPR) Cases Controls	SS 94 (68) 44 (49)	LS 31 (22) 40 (44)	LL 13 (9) 6 (7)	p 0.002	S 219 (79) 128 (71)	L 57 (21) 52 (29)	p 0.044
Sipila et al ²¹21 Sipilä T, Kananen L, Greco D, Donner J, Silander K, Terwilliger JD, et al. An Association Analysis of Circadian Genes in Anxiety Disorders. Biol Psychiatry. 2010;67(12):1163-70. DOI: 10.1016/j.biopsych.2009.12.011 https://doi.org/10.1016/j.biopsych.2009....	BCL2 Cases Controls	TT -	TC -	CC -		T 0.5825 0.4550	C 0.4175 0.5450	0.0029
Sipilä et al ²¹21 Sipilä T, Kananen L, Greco D, Donner J, Silander K, Terwilliger JD, et al. An Association Analysis of Circadian Genes in Anxiety Disorders. Biol Psychiatry. 2010;67(12):1163-70. DOI: 10.1016/j.biopsych.2009.12.011 https://doi.org/10.1016/j.biopsych.2009....	DRD2 Cases Controls	CC -	CA -	AA -	p	C 0.1931 0.3191	A 0.8069 0.6809	p 0.0010
Molina et al ²²22 Molina E, Cervilla J, Rivera M, Torres F, Bellon JA, Moreno B, et al. Polymorphic variation at the serotonin 1-A receptor gene is associated with comorbid depression and generalized anxiety. Psychiatr Genet. 2011;21(4):195-201. DOI: 10.1097/YPG.0b013e3283457a48 https://doi.org/10.1097/YPG.0b013e328345...	HTR1A Cases Controls	GG 22 (26) 243 (25)	GC 52 (61) 464 (48)	CC 11 (13) 267 (27)	p 0.010	G 96 (57) 950 (49)	C 74 (43) 998 (51)	p 0.054
Wang et al ²⁵25 Wang Y, Zhang H, Li Y, Wang Z, Fan Q, Yu S, et al. BDNF Val66Met polymorphism and plasma levels in Chinese Han population with obsessive-compulsive disorder and generalized anxiety disorder. J Affect Disord. 2015;186:7-12. DOI: 10.1016/j.jad.2015.07.023. https://doi.org/10.1016/j.jad.2015.07.02...	BDNF Cases Controls	GG 28 (25.9) 24 (24.2)	GA 55 (50.9) 54 (54.5)	AA 41 (27.7) 21 (21.2)	p 0.87	G 111 (51.4) 102 (51.5)	A 105 (48.6) 96 (48.5)	p 0.98
You et al ²⁶26 You JS, Hu SY, Chen B, Zhang HG. Serotonin transporter and tryptophan hydroxylase gene polymorphisms in Chinese patients with generalized anxiety disorder. Psychiatr Genet. 2005;15(1):7-11. DOI: 10.1097/00041444-200503000-00002 https://doi.org/10.1097/00041444-2005030...	5HTT (VNTR) Cases Controls	12/12 109 (79) 70 (78)	12/10 26 (19) 19 (21)	10/10 3 (2) 1 (1)	p 0.778	12 244 (88) 159 (88)	10 32 (12) 21 (12)	p 0.981
You et al ²⁶26 You JS, Hu SY, Chen B, Zhang HG. Serotonin transporter and tryptophan hydroxylase gene polymorphisms in Chinese patients with generalized anxiety disorder. Psychiatr Genet. 2005;15(1):7-11. DOI: 10.1097/00041444-200503000-00002 https://doi.org/10.1097/00041444-2005030...	TPH (A218C) Cases Controls	AA 31 (22) 18 (20)	AC 73 (53) 50 (56)	CC 34 (25) 22 (24)	p 0.893	A 135 (49) 86 (48)	C 141 (51) 94 (52)	p -

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