Editing GABA receptor (section)

== GABA receptor gene polymorphisms ==
Two separate genes on two chromosomes control GABA synthesis - glutamate decarboxylase and alpha-ketoglutarate decarboxylase genes - though not much research has been done to explain this polygenic phenomenon.<ref>{{Cite journal|date=2020-01-01|title=GABA synthesis mediated by γ-aminobutanal dehydrogenase in Synechocystis sp. PCC6803 with disrupted glutamate and α-ketoglutarate decarboxylase genes|url=https://www.sciencedirect.com/science/article/abs/pii/S0168945219310623|journal=Plant Science|language=en|volume=290|pages=110287|doi=10.1016/j.plantsci.2019.110287|issn=0168-9452|last1=Kanwal|first1=Simab|last2=Incharoensakdi|first2=Aran|pmid=31779897|s2cid=204162907|url-access=subscription}}</ref> GABA receptor genes have been studied more in depth, and many have hypothesized about the deleterious effects of polymorphisms in these receptor genes. The most common single nucleotide polymorphisms (SNPs) occurring in GABA receptor genes rho 1, 2, and 3 (GABBR1, GABBR2, and GABBR3) have been more recently explored in literature, in addition to the potential effects of these polymorphisms. However, some research has demonstrated that there is evidence that these polymorphisms caused by single base pair variations may be harmful.

It was discovered that the minor allele of a single nucleotide polymorphism at GABBR1 known as rs1186902 is significantly associated with a later age of onset for migraines,<ref>{{Cite journal|title=Gamma-Aminobutyric Acid (Gaba) Receptors Rho (Gabrr) Gene Polymorphisms and Risk for Migraine|journal=Headache: The Journal of Head and Face Pain|year = 2017|doi=10.1111/head.13122|last1 = García-Martín|first1 = Elena|last2 = Martínez|first2 = Carmen|last3 = Serrador|first3 = Mercedes|last4 = Alonso-Navarro|first4 = Hortensia|last5 = Navacerrada|first5 = Francisco|last6 = Esguevillas|first6 = Gara|last7 = García-Albea|first7 = Esteban|last8 = Agúndez|first8 = José A. G.|last9 = Jiménez-Jiménez|first9 = Félix Javier|volume = 57|issue = 7|pages = 1118–1135|pmid = 28699326|s2cid = 12303665}}</ref> but for the other SNPs, no differences were discovered between genetic and allelic variations in the control vs. migraine participants. Similarly, in a study examining SNPs in rho 1, 2, and 3, and their implication in essential tremor, a nervous system disorder, it was discovered that there were no differences in the frequencies of the allelic variants of polymorphisms for control vs. essential tremor participants.<ref>{{Cite journal|title=Gamma-aminobutyric acid (GABA) receptor rho (GABRR) polymorphisms and risk for essential tremor|journal=Journal of Neurology|year = 2011|doi=10.1007/s00415-010-5708-z|last1 = García-Martín|first1 = Elena|last2 = Martínez|first2 = Carmen|last3 = Alonso-Navarro|first3 = Hortensia|last4 = Benito-León|first4 = Julián|last5 = Lorenzo-Betancor|first5 = Oswaldo|last6 = Pastor|first6 = Pau|last7 = Puertas|first7 = Inmaculada|last8 = Rubio|first8 = Lluisa|last9 = López-Alburquerque|first9 = Tomás|last10 = Agúndez|first10 = José A. G.|last11 = Jiménez-Jiménez|first11 = Félix Javier|volume = 258|issue = 2|pages = 203–211|pmid = 20820800|s2cid = 22082250}}</ref> On the other hand, research examining the effect of SNPs in participants with restless leg syndrome found an "association between GABRR3rs832032 polymorphism and the risk for RLS, and a modifier effect of GABRA4 rs2229940 on the age of onset of RLS" - the latter of which is a modifier gene polymorphism.<ref>{{Cite journal|title=Gamma-aminobutyric acid (GABA) receptors genes polymorphisms and risk for restless legs syndrome|journal=The Pharmacogenomics Journal|year = 2018|doi=10.1038/s41397-018-0023-7|last1 = Jiménez-Jiménez|first1 = Félix Javier|last2 = Esguevillas|first2 = Gara|last3 = Alonso-Navarro|first3 = Hortensia|last4 = Zurdo|first4 = Martín|last5 = Turpín-Fenoll|first5 = Laura|last6 = Millán-Pascual|first6 = Jorge|last7 = Adeva-Bartolomé|first7 = Teresa|last8 = Cubo|first8 = Esther|last9 = Navacerrada|first9 = Francisco|last10 = Amo|first10 = Gemma|last11 = Rojo-Sebastián|first11 = Ana|last12 = Rubio|first12 = Lluisa|last13 = Díez-Fairén|first13 = Mónica|last14 = Pastor|first14 = Pau|last15 = Calleja|first15 = Marisol|last16 = Plaza-Nieto|first16 = José Francisco|last17 = Pilo-De-La-Fuente|first17 = Belén|last18 = Arroyo-Solera|first18 = Margarita|last19 = García-Albea|first19 = Esteban|last20 = Agúndez|first20 = José A. G.|last21 = García-Martín|first21 = Elena|volume = 18|issue = 4|pages = 565–577|pmid = 29720720|s2cid = 13756330}}</ref> The most common GABA receptor SNPs do not correlate with deleterious health effects in many cases, but do in a few.

One significant example of a deleterious mutation is the major association between several GABA receptor gene polymorphisms and schizophrenia. Because GABA is integral to the release of inhibitory neurotransmitters which produce a calming effect and play a role in reducing anxiety, stress, and fear, it is not surprising that polymorphisms in these genes result in more consequences relating to mental health than to physical health. Of an analysis on 19 SNPs on various GABA receptor genes, five SNPs in the GABBR2 group were found to be significantly associated with schizophrenia,<ref>{{Cite journal|last1=Lo|first1=W.-S.|last2=Lau|first2=C.-F.|last3=Xuan|first3=Z.|last4=Chan|first4=C.-F.|last5=Feng|first5=G.-Y.|last6=He|first6=L.|last7=Cao|first7=Z.-C.|last8=Liu|first8=H.|last9=Luan|first9=Q.-M.|last10=Xue|first10=H.|date=June 2004|title=Association of SNPs and haplotypes in GABA A receptor β 2 gene with schizophrenia|journal=Molecular Psychiatry|language=en|volume=9|issue=6|pages=603–608|doi=10.1038/sj.mp.4001461|pmid=14699426|s2cid=5567422|issn=1476-5578|doi-access=}}</ref> which produce the unexpected haplotype frequencies not found in the studies mentioned previously.

Several studies have verified association between alcohol use disorder and the rs279858 polymorphism on the GABRA2 gene e, and higher negative alcohol effects scores for individuals who were homozygous at six SNPs.<ref>{{Cite journal|last1=Koulentaki|first1=Mairi|last2=Kouroumalis|first2=Elias|date=2018-06-01|title=GABAA receptor polymorphisms in alcohol use disorder in the GWAS era|url=https://doi.org/10.1007/s00213-018-4918-4|journal=Psychopharmacology|language=en|volume=235|issue=6|pages=1845–1865|doi=10.1007/s00213-018-4918-4|pmid=29721579|s2cid=13744792|issn=1432-2072|url-access=subscription}}</ref> Furthermore, a study examining polymorphisms in the GABA receptor beta 2 subunit gene found an association with schizophrenia and bipolar disorder, and examined three SNPs and their effects on disease frequency and treatment dosage.<ref>{{Cite journal|last1=Chen|first1=Jianhuan|last2=Tsang|first2=Shui-Ying|last3=Zhao|first3=Cun-You|last4=Pun|first4=Frank W.|last5=Yu|first5=Zhiliang|last6=Mei|first6=Lingling|last7=Lo|first7=Wing-Sze|last8=Fang|first8=Shisong|last9=Liu|first9=Hua|last10=Stöber|first10=Gerald|last11=Xue|first11=Hong|date=2009-12-01|title=GABRB2 in schizophrenia and bipolar disorder: disease association, gene expression and clinical correlations|url=https://portlandpress.com/biochemsoctrans/article/37/6/1415/65028/GABRB2-in-schizophrenia-and-bipolar-disorder|journal=Biochemical Society Transactions|language=en|volume=37|issue=6|pages=1415–1418|doi=10.1042/BST0371415|pmid=19909288|s2cid=10742771 |issn=0300-5127|url-access=subscription}}</ref> A major finding of this study was that functional psychosis should be conceptualized as a scale of phenotypes rather than distinct categories.