Table 1.

Candidate Genes, Mechanisms of Action and Rational for Inclusion in Model Testing

Gene: SNPs that were tested in Model testing*	Gene location	Description of Mechanism	Prior Associations of Gene with Pain
FKBP5: rs16878806; rs16879378; rs145774; rs2817032	Chromosome 6, 35573585- 35728583 bp	The FKBP5 gene is involved in the regulation of plasma cortisol following stress such as that associated with pain.	In prior research (Bortsov, Diatchenko, & McLean, 2014) this gene was associated with musculoskeletal pain following traumatic motor vehicle accidents.
BDNF: rs11602246	Chromosome 11, 27, 654, 892- 27, 722, 057 bp	The BDNF gene is a neurotrophin that promotes the survival and proliferation of nerve cells and is involved in inflammation. BDNF is an important central pain mediator.	In prior research (Cheng et al., 2011; Ding et al., 2014)3 (Forsgren, Grimsholm, Dalén, & Rantapää-Dahlqvist, 2011) this gene was associated with neuropathic pain as well as pain from rheumatoid arthritis.
NTRK1 (No SNPs from this gene were significantly associated with pain so were not included in model testing)	Chromosome 1, 156, 815, 749- 156, 881, 849 bp	The NTRK1 gene provides instructions for making a protein that is essential for the development and survival of nerve cells (neurons), especially those that transmit information about sensations such as pain, temperature, and touch (sensory neurons).	In prior research (Mardy et al., 1999) there was evidence that mutations in the NTRK1 gene cause congenital insensitivity to pain with anhidrosis, a condition characterized by the inability to feel pain and decreased or absent sweating.
NTRK2: rs4142910; rs1140755; rs12340748; rs10780688; rs7019555; rs4631550; rs1565447; rs1565446; rs1565445; rs10125469; rs7045296; rs7030960; rs7857957; rs1490406; rs1490405; rs1490404; rs10123600; rs41277883; rs2013566	Chromosome 9, 84, 668, 501- 85, 027, 069 bp	The NTRK2 gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family and is involved with neuron survival.	In prior research (Lin, Ro, Wang, & Chen, 2011; Renn, Leitch, & Dorsey, 2009) this gene was associated with nociception and the ability to feel inflammatory pain.
NTRK3: rs177652811; rs11634388; rs16941001; rs16941392; rs8033396; rs1863482; rs11073768; rs7172053	Chromosone 15, 87, 859, 751–88, 256, 768 bp	The NTRK3 gene is involved with mediating the effects of neurotrophic factor including neuronal differentiation and survival.	In prior research (Ghilardi et al., 2011; Tender, Kaye, Li, & Cui, 2011) this gene was associated with neuropathic pain in animal models and skeletal pain in human models.
COMT (No SNPs from this gene were significantly associated with pain or function so were not included in model testing)	Chromosome 22, 19, 941, 739–19, 969, 974 bp	The COMT gene mediates the inactivation of catecholamine neurotransmitters, including dopamine, adrenaline, and noradrenaline. Reduced COMT enzymatic activity results in increased pain sensitivity and sensations of pain.	In prior research (Belfer et al., 2013; Bortsov et al., 2014; Cohen, Neumann, Glazer, Ebstein, & Buskila, 2009; James, 2013; Smith et al., 2014) this gene was consistently associated with chronic pain, musculoskeletal pain and other conditions with pain as a symptom. COMT has been noted to confer protection or decrease pain and help with the modulation of analgesic efficacy.
SLC6A4 (No SNPs from this gene were significantly associated with pain or function so were not included in model testing)	Chromosome 17 30194319- 30236002 bp	The SLC6A4 gene is associated with transporting the neurotransmitter serotonin from synaptic spaces into presynaptic neurons.	In prior research (Hooten, Hartman, Black, Laures, & Walker, 2013; Kumar, Ranjan, Mittal, & Ghoshal, 2012; Lindstedt et al., 2011) this gene was associated with the pain that occurred from irritable bowel disease. In addition SLC6A4 was associated with chronic pain disorders and with heat pain.
OXTR: rs2270465; rs401015	Chromosome 3,. 8, 750, 408–8, 769, 628 bp	The OXTR gene belongs to the G- protein coupled receptor family and acts as a receptor for oxytocin. Receptors in the central nervous system modulate behaviors such as stress and anxiety; social memory; sexual aggression and bonding. The OXTR gene has also been associated with optimism, mastery, and self-esteem.	In prior research (Osherovich, 2011; Russo et al., 2012) this gene was associated with hyperalgesia in animal models. OXTR was also associated with the ability to cope with pain and thus is being considered as influential with regard to treatment modalities.
DRD4 (No SNPs from this gene were significantly associated with pain or function so were not included in model testing)	Chromosome 11, 637, 305 to 640, 706 bp	The DRD4 gene is associated with the neurotransmitter dopamine. It is linked to many neurological and psychiatric conditions including Parkinson’s Disease, addictive behaviors, eating disorders and schizophrenia as well as being associated with chronic pain.	In prior research (Buskila, Cohen, Neumann, & Ebstein, 2004; Limer, Nicholl, Thomson, & McBeth, 2008; Mercado, Barjola, Fernández-Sánchez, Guerra, & Gómez-Esquer, 2013) this gene was associated with widespread pain, such as that noted in individuals with fibromyalgia.
MAOA(No SNPs from this gene were significantly associated with pain or function so were not included in model testing)	X chromosome, 43, 654, 906–43, 746, 823 bp	The MAOA gene encodes mitochondrial enzymes which catalyze the oxidative deamination of amines, such as dopamine, norepinephrine, and serotonin.	In prior research (Di Lorenzo et al., 2014; Kim, Lee, Rowan, Brahim, & Dionne, 2006) this gene was associated with trigeminal pain disorders as well as post-surgical pain.

Key:

COMT = catecholamine-O-methyltransferase

BDNF = Brain Derived Neurotrophic Factor

NTRK1 = neurotrophic tyrosine kinase, receptor, type 1.

NTRK2 = neurotrophic tyrosine kinase, receptor, type 2.

NTRK3 = neurotrophic tyrosine kinase, receptor, type 3.

SLC6A4= Solute Carrier Family 6 (Neurotransmitter Transporter), Member 4¹

OXTR= oxytocin receptor

DRD4= Dopamine receptor gene

MAOA= monoamine oxidase A

FKBP5 = K506 binding protein 5

^*Bolded SNPs are those that remained significant in model testing.