I am a cis-gender, heterosexual white male. According to my 23andme results, I am 55.6% Dutch and German (mostly Dutch), 30.7% British Isles (I have Scottish ancestry on my father’s side) and 13.7% Danish.
My maternal haplogroup is H5a1 and my paternal haplogroup is R-S660. I have 315 Neanderthal variants, putting me in the 95th percentile (in other words, I have more Neanderthal DNA in my genome than 95% of other 23andme users).
The following is from research I have done using the raw SNP data available from my 23andme results. It can be a bit technical. I use the rs accession numbers for the polymorphisms. Bold+underline is the gene; underline is my particular SNP results; the rest is information gleaned from research papers available online.
Serotonin 5-HT1A Receptor
The C(-1019)G rs6295 SNP has been investigated for association with suicide attempts, and psychiatric disorders. One study found an association of the variant with schizophrenia. Some studies associate homozygous C(-1019)G genotype with depression. The polymorphism has also been investigated for links to personality traits. Persons with the G-allele of the polymorphism may have higher personality score for the NEO PI-R Neuroticism (more likely to experience such feelings as anxiety, worry, fear, anger, frustration, envy, jealousy, guilt, depressed mood, and loneliness) and TPQ Harm Avoidance (excessive worrying, pessimism, shyness, and being fearful, doubtful, and easily fatigued) traits. One study found higher score on Temperament and Character Inventory self-transcendence scale for G-allele subjects among mood disorder patients (self-transcendence is the capacity to expand self-boundaries intrapersonally (toward greater awareness of one’s philosophy, values, and dreams), interpersonally (to relate to others and one’s environment), temporally (to integrate one’s past and future in a way that has meaning for the present), and transpersonally (to connect with dimensions beyond the typically discernible world)).
Dopamine D1 Receptor
DRD2/ANKK1 Taq1A polymorphism (rs1800497, Glu713Lys) is located ~10 kb downstream from the DRD2 gene (placing it in the 3`-UTR of the DRD2 gene) in the ankyrin repeat and kinase domain containing 1 (ANKK1) gene. The A1 allele of rs1800497 has consistently been implicated in addiction disorders (Noble, 2000; Smith et al., 2008; Chen et al., 2011) and has also been reported to be a risk factor for depression. In a longitudinal study of 2347 adult males, the A1 allele was associated with an increased risk of developing depressive symptoms at follow-up (odds ratio 2.55; Roetker et al., 2012). The Taq1A polymorphism or a variant in linkage disequilibrium with Taq1A appears to affect D2 receptor binding, perhaps explaining the reported associations between Taq1A and psychiatric and addiction disorders. Relative to the A2 allele, the A1 allele has been associated with reduced striatal glucose metabolism (Noble et al., 1997) and reduced binding of the D2/3 receptor antagonist, [11C]raclopride, in studies of healthy subjects (Thompson et al., 1997; Pohjalainen et al., 1998; Jonsson et al., 1999).
Jonathan Savitz, Colin A. Hodgkinson, Chantal Martin-Soelch, Pei-Hong Shen, Joanna Szczepanik, Allison
- Nugent, Peter Herscovitch, Anthony A. Grace, David Goldman, and Wayne C. Drevets. DRD2/ANKK1 Taq1A polymorphism (rs1800497) has opposing effects on D2/3 receptor binding in healthy controls and patients with major depressive disorder.
Homozygosity for the normal GG variants in rs6277 are thought to have increased chances for alcohol dependence compared to those who are heterozygous GA or homozygous AA with the minor “A” allele.
The minor “A” allele in rs1076560 causes altered splicing of DRD2 protein, which decreases the ratio of D2S and D2L and subsequently increases dopamine signaling. The D2 long isoform (D2L) is mainly postsynaptic and is a target for haloperidol, and the D2 short (D2S) isoform is mainly presynaptic and serves as an autoreceptor regulating (inhibiting) dopamine synthesis and release. The minor “A” allele has been associated with lower working memory and schizophrenia. The minor “A” allele is also found to increase risk for psychiatric disorders such as schizophrenia and also the risk for developing substance dependence.
The minor “T” allele in rs1079597 reduces the number of dopamine D2 receptors (in striatum) and is associated with Tourette Syndrome.
Heterozygosity TC in rs1125394 causes a slight decrease in the number of D2S receptors. The minor “T” allele is associated with increased risk of substance addiction.
Heterozygosity CA in rs2283265 causes a slight decrease in the number of D2S receptors. The minor “A” allele is associated with Increased risk of schizophrenia, decreased performance of working memory and attentional control tasks (AA and AC), increased susceptibility of cocaine and Heroin addiction (AA and AC), and a tendency to make negative (poor) life decisions.
Heterozygous for rs4680 Val158Met; homozygous for rs165599 minor “G” allele; heterozygous for rs737865 intron variant.
The COMT gene codes for the COMT enzyme, which breaks down dopamine in the brain’s prefrontal cortex. The wild-type allele is a (G), coding for a valine amino acid (Val158); the (A) substitution polymorphism changes the amino acid to a methionine (Val158Met). This alters the structure of the resultant enzyme such that its activity is only 25% of the wild type. As a result, A allele carriers have more dopamine in their prefrontal cortex, which may be responsible for many of the neuropsychological associations listed below.
23andMe blog summarizes the alleles at this SNP as:
- rs4680(A) = Worrier. Met, more exploratory, lower COMT enzymatic activity, therefore higher dopamine levels; lower pain threshold, enhanced vulnerability to stress, yet also more efficient at processing information under most conditions
- rs4680(G) = Warrior. Val, less exploratory, higher COMT enzymatic activity, therefore lower dopamine levels; higher pain threshold, better stress resiliency, albeit with a modest reduction in executive cognition performance under most conditions
Roughly speaking, the predominant wisdom (known colloquially as the warrior/worrier hypothesis; summary at [PMID 17008817]) posits that people with Val alleles have increased COMT activity and lower prefrontal extracellular dopamine compared with those with the Met substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy). Under conditions of increased dopamine release (eg, stress), individuals with Val158 alleles may have improved dopaminergic transmission and better performance, while individuals with Met158 alleles may have less efficient neurotransmission and worse performance. Some evidence suggests that Val158 alleles are associated with schizophrenia, while Met158 alleles are associated with anxiety.
We observed a modest but significant association between the GG SNP rs165599 and Bipolar Disorder I, with the GG genotype being over-represented in cases versus controls. (odds ratio, OR = 2.41). Further, we found a relationship between the minor “G” allele at this SNP and poorer performance on measures of verbal memory.
The rs737865 minor “C” allele and rs165599 minor “G” allele being associated with lower expression of COMT mRNA in the human brain. The rs737865 minor “C” allele is associated with increased reading comprehension.
COMT and DRD2 Synergistic Pleiotropy for Working Memory
Burst firing of ventral tegmental area (VTA) neurons causes synaptic dopamine release into pyramidal cells of the prefrontal cortex (PFC). Because these cells contain little dopamine transporter (DAT), the dopamine diffuses out of the synapse to bind extrasynaptic D1 receptors where it is inactivated by COMT. The higher activity Val158 COMT allele breaks down the dopamine before it diffuses out of the synapse, which decreases D1 receptor activation, shifting the balance to favor intrasynaptic D2 receptor activation. Cognitive performance may be critically dependent on the D1/D2 binding ratio, with a relative lack of D1-signaling causing impulsivity, distractibility and poor working memory performance with schizophrenia at the extreme end (Winterer & Weinberger 2004). A relative lack of D2-signaling, on the other hand, may fail to signal the presence of reward information, a signal that is required to engage the PFC in updating its working memory system (Weinberger et al. 2001). The rs1800497 Taq1A allele of the D2 receptor decreases the expression level of the D2 receptor, which would allow dopamine to diffuse out of the synapse and activate the D1 receptors. The Met158/Val158 heterozygotes increased the benefit to working memory by more slowly digesting dopamine, allowing even more of the neurotransmitter to diffuse out of the synapse and activate D1 receptors.
María Florencia Gosso. Common Genetic Variants Underlying Cognitive Ability. PhD Thesis. 2007.
Muscarinic Acetylcholine Receptor M2
Homozygous for rs324650 minor “T” intron variant; homozygous for rs324640 minor “G” intron variant.
M2 muscarinic receptors act via a Gi-protein coupled receptor, which causes a decrease in cAMP in the cell, generally leading to inhibitory-type effects. They appear to serve as autoreceptors – a type of receptor located in the membranes of presynaptic nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the autoreceptor sits. Similarly, a heteroreceptor is sensitive to neurotransmitters and hormones that are not released by the cell on which it sits. A given receptor can act as either an autoreceptor or a heteroreceptor, depending upon the type of transmitter released by the cell on which it is embedded. Studies show an association between T/T homozygosity in the rs324650 and G/G homozygosity in the rs324640 of the CHRM2 gene and intelligence. In one study of ~300 Caucasians, the T/T and G/G homozygous genotypes appeared to typically have a 4-point higher IQ than the A/T or A/G heterozygous genotypes, which had a 4-point higher IQ (on average) than the A/A homozygous genotypes of either SNP. Earlier work had observed that the T/T rs324650 SNP increased chances of alcohol dependence.
Synaptosomal Associated Protein of 25 kD
Homozygous for rs363050 minor “A” variant in 5`-UTR; Homozygous for rs363039 minor “G” intron variant; homozygous for rs363043 C (WT) intron variant.
The synaptosomal associated protein of 25 kD (SNAP25) gene plays an integral role in synaptic transmission, and is differentially expressed in the mammalian brain in the neocortex, hippocampus, anterior thalamic nuclei, substantia nigra, and cerebellar granular cells. SNAP25 is a component of the SNARE complex, which is central to synaptic vesicle exocytosis, and, by directly interacting with different calcium channel subunits, it negatively modulates neuronal voltage-gated calcium channels, thus regulating intracellular calcium dynamics. SNAP25 may also regulate postsynaptic receptor trafficking, spine morphogenesis, and plasticity. Studies have suggested a possible involvement of SNAP25 in learning and memory, both of which are key components of human intelligence. In addition, the SNAP25 gene lies in a linkage area implicated previously in human intelligence.
The minor “A” allele of rs363050 SNP was associated with an increase of 2.84 IQ points (Gosso, 2007).
The minor “G” allele of rs363039 SNP was associated with intelligence, but weaker than rs363050 (Gosso, 2007). Association with variation in IQ in normal population; verbal performances in women; working memory capacity; cognitive traits in autistic children
The major “C” allele of rs363043 SNP is the wild type. The T/T genotype averages several IQ points higher than the C/T genotype, which averages several IQ points higher than the C/C genotype.