Table 1.
Replicable risk KTN1 SNPs significantly associated with both putamen GMV and alcohol and drug co-dependence in five independent samples
| SNP | Genomic position at 14q |
Risk allele |
European-American | European-Australian | African-American (1st) | African-American (2nd) | ENIGMA2 Data | Bioinfomatics | Associated phenotypes reported In literature |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Alcohol and marijuana | Alcohol and nicotine | Alcohol and cocaine | Alcohol and marijuana | Putamen GMV | ||||||||||||||
| Frequency | (n=1,881) | Frequency | (n=6,438) | Frequency | (n=867) | Frequency | (n=1,023) | (n=13,145) | ||||||||||
| Case | Control | p | Observed | Expected | p | Case | Control | p | Case | Control | p | β | p | |||||
| rs946066 | 55002625 | C | 0.93 | 0.89 | 1.4×10−4 | 0.89 | 0.88 | 0.021 | 0.75 | 0.73 | - | 0.62 | 0.57 | - | 3.5 | - | -- | -- |
| rs11158044 | 55004557 | C | 0.85 | 0.81 | 2.5×10−3 | 0.78 | 0.77 | 0.036 | 0.73 | 0.73 | - | 0.73 | 0.72 | - | 14.1 | 0.050 | -- | -- |
| rs56969685 | 55004865 | C | 0.85 | 0.81 | 2.5×10−3 | 0.78 | 0.77 | 0.036 | 0.75 | 0.75 | - | 0.79 | 0.79 | - | 15.6 | 0.036 | -- | -- |
| rs2181740 | 55052059 | A | 0.61 | 0.56 | 3.5×10−3 | 0.51 | 0.51 | - | 0.32 | 0.35 | - | 0.11 | 0.06 | 0.012 | 27.0 | 4.5×10−6 | lncRNA | -- |
| rs2341883 | 55054765 | A | 0.69 | 0.63 | 1.1×10−3 | 0.59 | 0.59 | - | 0.45 | 0.45 | - | 0.13 | 0.06 | 0.011 | 17.9 | 3.8×10−3 | lncRNA | prostate cancer |
| rs10132888 | 55063703 | A | 0.61 | 0.56 | 0.011 | 0.53 | 0.53 | - | 0.38 | 0.42 | - | 0.28 | 0.21 | 6.1×10−3 | 26.0 | 1.2×10−5 | lncRNA | -- |
| rs10148298 | 55067916 | T | 0.92 | 0.88 | 6.4×10−3 | 0.89 | 0.88 | 0.037 | 0.84 | 0.84 | - | 0.75 | 0.88 | - | 31.5 | 2.7×10−5 | lncRNA | GMV, MjD |
| rs4901578 | 55069085 | G | 0.88 | 0.86 | 0.028 | 0.86 | 0.85 | 0.032 | 0.89 | 0.89 | - | 0.70 | 0.70 | - | 43.2 | 4.1×10−8 | lncRNA, CTCF | GMV |
| rs4901580 | 55069173 | G | 0.88 | 0.85 | 0.025 | 0.85 | 0.84 | 0.033 | 0.86 | 0.86 | - | 0.76 | 0.76 | - | 43.2 | 4.1×10−8 | lncRNA, CTCF | -- |
| rs11847588 | 55095399 | G | 0.86 | 0.82 | 0.016 | 0.83 | 0.82 | 0.032 | 0.84 | 0.84 | - | 0.79 | 0.79 | - | 40.6 | 4.3×10−7 | lncRNA | MjD |
| rs2341884 | 55095553 | C | 0.86 | 0.82 | 0.016 | 0.83 | 0.82 | 0.032 | 0.84 | 0.84 | - | 0.85 | 0.85 | - | 40.5 | 4.6×10−7 | lncRNA | -- |
| rs4143891 | 55095928 | G | 0.86 | 0.82 | 0.016 | 0.83 | 0.82 | 0.032 | 0.86 | 0.86 | - | 0.79 | 0.79 | - | 40.5 | 4.5×10−7 | lncRNA | -- |
| rs6573040 | 55097568 | T | 0.83 | 0.80 | 0.029 | 0.80 | 0.79 | 0.021 | 0.80 | 0.80 | - | 0.82 | 0.82 | - | 44.0 | 5.5×10−9 | lncRNA | -- |
| rs12589867 | 55115552 | G | 0.79 | 0.77 | 0.040 | 0.79 | 0.78 | 0.036 | 0.93 | 0.93 | - | -- | -- | - | 26.5 | 7.0×10−5 | lncRNA, TFBS | -- |
| rs60233569 | 55229977 | A | 0.83 | 0.78 | 0.016 | 0.88 | 0.87 | 0.035 | 0.75 | 0.75 | - | 0.88 | 0.88 | - | 25.7 | 9.7×10−5 | cis-eQTL | -- |
| rs12895072 | 55238252 | C | 0.88 | 0.84 | 8.8×10−3 | 0.84 | 0.83 | 0.025 | 0.97 | 0.95 | 0.049 | 0.99 | 0.99 | - | 41.1 | 3.6×10−7 | enhancer | cognitive dysfunction |
| rs1953354 | 55255787 | C | 0.78 | 0.75 | 2.6×10−3 | 0.77 | 0.75 | 4.2×10−3 | 0.70 | 0.69 | - | 0.71 | 0.68 | - | 45.2 | 4.2×10−11 | -- | -- |
| rs8014725 | 55256706 | A | 0.58 | 0.56 | - | 0.51 | 0.49 | 0.033 | 0.17 | 0.19 | - | 0.29 | 0.24 | 0.025 | 55.6 | 2.2×10−21 | cis-eQTL | GMV, PD |
| rs2342588 | 55266792 | T | 0.57 | 0.55 | - | 0.50 | 0.48 | 0.025 | 0.76 | 0.74 | - | 0.67 | 0.61 | 0.046 | 56.1 | 1.9×10−21 | cis-eQTL | PD |
| rs2342589 | 55266821 | G | 0.57 | 0.55 | - | 0.50 | 0.48 | 0.025 | 0.76 | 0.74 | - | 0.67 | 0.61 | 0.046 | 56.1 | 1.9×10−21 | cis-eQTL | PD |
| rs8017172** | 55268801 | G | 0.60 | 0.58 | - | 0.56 | 0.54 | 0.023 | 0.20 | 0.22 | - | 0.20 | 0.20 | - | 60.4 | 5.7×10−24 | cis-eQTL, CTCF | GMV, PD |
| rs945270** | 55270226 | C | 0.60 | 0.58 | - | 0.61 | 0.59 | 6.6×10−3 | 0.16 | 0.19 | - | 0.02 | 0.02 | - | 48.9 | 1.1×10−33 | cis-eQTL | GMV, PD, ADHD, heroin |
| rs1959087* | 55270950 | T | 0.69 | 0.68 | - | 0.66 | 0.64 | 4.8×10−4 | 0.79 | 0.79 | - | 0.88 | 0.86 | - | 59.4 | 1.1×10−20 | -- | PD |
| rs17253792** | 55274783 | T | 0.94 | 0.93 | - | 0.94 | 0.93 | 0.058 | -- | -- | - | -- | -- | - | 52.8 | 1.9×10−7 | -- | GMV |
| rs7153309 | 55471330 | A | 0.89 | 0.86 | 0.028 | 0.93 | 0.92 | 0.022 | 0.45 | 0.47 | - | 0.24 | 0.15 | - | 7.9 | - | lncRNA | -- |
| rs12882780 | 55512345 | G | 0.97 | 0.95 | 0.042 | 0.98 | 0.97 | 3.3×10−3 | 0.99 | 0.99 | - | 0.97 | 0.97 | - | 8.6 | - | -- | MjD |
| rs1542577 | 55516009 | A | 0.91 | 0.89 | - | 0.89 | 0.89 | 0.044 | 0.98 | 0.96 | 0.032 | 0.97 | 0.95 | - | 14.5 | - | -- | -- |
The underline in the first column separates SNPs into two locations: 5’ and 3’ flanking regions. Four non-replicable risk SNPs are listed in Table 1:
this SNP is the most significant one in the European-Australians
these SNPs were reported to be GMV-associated. -, p>0.05; --, missing. ENIGMA2 data, imaging genomic data for subcortical structure; β, effect size for SNPs to control putamen volume. lincRNA, located in a long interspersed ncRNA sequence; TFBS, located in a transcription factor binding site; enhancer, located in an enhancer; CTCF, located in a transcriptional repressor CTCF binding site; cis-eQTL, this SNP significantly regulates KTN1 mRNA expression in putamen (p<0.05). Previously-reported associated phenotypes: GMV, gray matter volume; MjD, Marijuana dependence; PD, Parkinson’s disease; ADHD, attention deficit hyperactive disorder; heroin, heroin dependence. Detailed demographic information is available in these citations: Gelernter et al. Mol Psychiatry. 2014;19(1):41-49; Bierut et al. PNAS. 2010;107(11):5082-5087; Edenberg et al. ACER. 2010;34(5):840-852; Heath et al. Biol psychiatry. 2011;70(6):513-518; Hibar et al. Nature. 2015;520(7546):224-229.