Associations of BRAP polymorphisms with the risk of alcohol dependence and scores on the Alcohol Use Disorders Identification Test

Figures & data

Table 1 Clinical profiles of study subjects

Description	AD	Non-AD	P-value
N	459	455
Age (year; mean-range)	47.37 (21–80)	44.21 (20–79)	<0.001a
Gender (M/F)	410/49	351/104	<0.001b
AUDIT
Overall	27.90±7.39 (0–40)	8.58±6.36 (0–29)	<0.001a
Alcohol consumption	10.23±2.10 (0–12)	5.73±3.46 (0–12)	<0.001a
Alcohol dependence	7.37±3.26 (0–12)	0.99±1.50 (0–8)	<0.001a
Alcohol-related harm	10.29±3.54 (0–16)	1.85±2.58 (0–14)	<0.001a

Notes:

a P-value was calculated using t-test analysis.

b P-value was calculated using chi-square analysis.

Abbreviations: AD, alcohol dependence; AUDIT, Alcohol Use Disorders Identification Test; F, female; M, male.

Table 2 Follow-up analysis of BRAP polymorphisms with the risk of alcohol dependence in Korean subjects

Loci	Allele	Position (AA change)	GWAS P-value	MAF		Codominant			Dominant			Recessive		Statistical power (%)
				AD	Non- AD	OR (95% CI)	P-valuea	Pcorrb	OR (95% CI)	P-valuea	Pcorrb	OR (95% CI)	P-valuea
rs847895	A>G	Intron 3	–	0.336	0.300	1.22 (1.00–1.50)	0.05	NS	1.23 (0.94–1.60)	0.13	–	1.47 (0.94–2.31)	0.09	98.6
rs3782886	A>G	Exon 5 (R241R)	5.0×10^−6	0.041	0.159	0.19 (0.13–0.28)	1.29×10^−^Citation16	7.74×10^−^Citation16	0.19 (0.13–0.28)	9.84×10^−^Citation17	5.90×10^−^Citation16	–	–	25.2
rs3803171	G>T	Intron 5	–	0.452	0.393	1.28 (1.06–1.56)	0.01	NS	1.31 (0.99–1.74)	0.06	–	1.51 (1.06–2.15)	0.02	98.5
rs3742001	A>G	Intron 6	–	0.121	0.097	1.22 (0.89–1.67)	0.21	–	1.23 (0.89–1.71)	0.21	–	1.37 (0.25–7.58)	0.72	82.0
rs118186470	T>C	Exon 11 (R472K)	–	0.005	0.002	2.41 (0.43–13.46)	0.32	–	2.41 (0.43–13.46)	0.32	–	–	–	7.26
				Frequency
ht1				0.502	0.444	1.29 (1.07–1.56)	0.009	NS	1.34 (1.00–1.81)	0.05	NS	1.48 (1.07–2.04)	0.02	97.32

Notes: Boldface indicates P-value ⩽0.05. P-values of GWAS represent the codominant model, which includes the additive model, adjusted for age and sex as covariates.

a P-value of logistic analysis under additive model by adjusting for sex and age as covariates.

b P-value after Bonferroni correction for multiple testing.

Abbreviations: AA, amino acid; AD, alcohol dependence; BRAP, BRCA1-associated protein; GWAS, genome-wide association study; MAF, minor allele frequency; ht, haplotype.

Table 3 Association analysis of BRAP polymorphisms with the AUDIT and subcategorical scores in all study subjects (n=914)

Category	Loci	C/C		C/R		R/R		P-valuea	Pcorrb
		N	AUDIT score	N	AUDIT score	N	AUDIT score
AUDIT all	rs847895	424	17.46±11.96	399	18.57±11.91	91	20.85±10.96	0.01	NS
	rs3782886	736	20.36±11.12	173	9.94±11.08	5	1.20±1.64	9.94×10^−31	5.96×10^−30
	rs3803171	299	16.81±11.88	455	18.46±12.14	158	20.37±10.69	0.002	0.01
	ht1	250	16.54±11.96	463	18.43±12.20	201	20.09±10.71	0.0007	0.004
Alcohol consumption	rs847895	424	7.81±3.70	399	8.02±3.68	91	8.68±3.07	0.06	–
	rs3782886	736	8.73±3.15	173	5.06±3.91	5	0.40±0.55	3.30×10^−46	1.98×10^−45
	rs3803171	299	7.61±3.70	455	8.00±3.77	158	8.64±3.02	0.005	0.02
	ht1	250	7.29±3.88	463	7.98±3.73	201	8.89±2.84	3.36×10^−07	2.02×10^−6
Alcohol dependence	rs847895	424	3.92±4.05	399	4.36±4.13	91	4.78±3.91	0.02	NS
	rs3782886	736	4.74±4.06	173	2.01±3.35	5	0.00±0.00	1.95×10^−17	1.17×10^−16
	rs3803171	299	3.75±4.04	455	4.33±4.10	158	4.57±3.97	0.03	NS
	ht1	250	3.64±3.94	463	4.34±4.14	201	4.57±4.06	0.009	NS
Alcohol-related harm	rs847895	424	5.73±5.29	399	6.18±5.16	91	7.38±5.22	0.007	NS
	rs3782886	736	6.88±5.10	173	2.87±4.56	5	0.80±1.79	3.89×10^−22	2.34×10^−21
	rs3803171	299	5.45±5.16	455	6.12±5.29	158	7.16±5.07	0.001	0.007
	ht1	250	5.61±5.30	463	6.12±5.31	201	6.63±4.98	0.03	NS

Notes: C/C, C/R, and R/R mean major homozygote, heterozygote, and minor homozygote, respectively. AUDIT score is mean±SD. Boldface indicates P-value <0.05.

a P-value of linear regression analysis under additive model by adjusting for sex and age as covariates.

b P-value after Bonferroni correction for multiple testing.

Abbreviations: AUDIT, Alcohol Use Disorders Identification Test; BRAP, BRCA1-associated protein; ht, haplotype; NS, not significant.

Table 4 Association analysis of BRAP polymorphisms with the AUDIT and subcategorical scores in non-alcohol dependence subjects (n=455)

Category	Loci	C/C		C/R		R/R		P-valuea	Pcorrb
		N	AUDIT score	N	AUDIT score	N	AUDIT score
AUDIT all	rs847895	221	7.91±5.92	195	9.00±6.83	39	10.21±6.01	0.007	0.04
	rs3782886	315	10.26±6.23	135	4.91±4.88	5	1.20±1.64	1.40×10^−24	8.39×10^−24
	rs3803171	163	7.87±5.94	226	8.62±6.65	66	10.17±6.15	0.004	0.02
	ht1	138	7.44±6.35	230	8.52±6.47	87	10.53±5.65	0.0001	0.0006
Alcohol consumption	rs847895	221	5.57±3.43	195	5.76±3.56	39	6.49±3.05	0.11	–
	rs3782886	315	6.71±3.20	135	3.64±2.97	5	0.40±0.55	6.46×10^−32	3.87×10^−31
	rs3803171	163	5.49±3.37	226	5.67±3.58	66	6.53±3.17	0.02	NS
	ht1	138	4.97±3.58	230	5.61±3.42	87	7.24±2.89	1.02×10^−07	6.13×10^−7
Alcohol dependence	rs847895	221	0.81±1.33	195	1.14±1.62	39	1.33±1.66	0.006	NS
	rs3782886	315	1.22±1.59	135	0.50±1.11	5	0.00±0.00	2.59×10^−07	1.56×10^−6
	rs3803171	163	0.75±1.22	226	1.10±1.62	66	1.24±1.61	0.004	0.02
	ht1	138	0.89±1.45	230	1.06±1.60	87	0.99±1.26	0.58	–
Alcohol-related harm	rs847895	221	1.54±2.26	195	2.10±2.87	39	2.38±2.62	0.008	0.04
	rs3782886	315	2.33±2.76	135	0.77±1.71	5	0.80±1.79	3.88×10^−10	2.32×10^−9
	rs3803171	163	1.63±2.38	226	1.86±2.56	66	2.39±3.04	0.03	NS
	ht1	138	1.58±2.62	230	1.85±2.53	87	2.30±2.63	0.04	NS

Notes: C/C, C/R, and R/R mean major homozygote, heterozygote, and minor homozygote, respectively. AUDIT score is mean±SD. Boldface indicates P-value <0.05.

a P-value of linear regression analysis under additive model by adjusting for sex and age as covariates.

b P-value after Bonferroni correction for multiple testing.

Abbreviations: AUDIT, Alcohol Use Disorders Identification Test; BRAP, BRCA1-associated protein; ht, haplotype; NS, not significant.

Figure S1 Haplotypes and LD structures of BRAP and PRMT8.

Notes: (A) Haplotypes of and (B) LDs among BRAP polymorphisms. (C) Haplotypes of and (D) LDs among PRMT8 polymorphisms.

Abbreviations: BRAP, BRCA1-associated protein; LD, linkage disequilibrium; PRMT8, protein arginine methyltransferase.

Table S1 Association analysis between PRMT8 SNPS and alcohol dependence subjects (n=914)

Loci	Allele	Position	GWAS P-value	MAF		Codominant		Dominant		Recessive		Statistical power (%)
				AL	Non-AL	OR (95% CI)	P-value*	OR (95% CI)	P-value*	OR (95% CI)	P-value*
rs34596546	T>C	Intron	–	0.038	0.032	1.17 (0.70–1.97)	0.55	1.17 (0.70–1.97)	0.55	–	–	43.6
rs7303822	T>G	Intron	–	0.090	0.092	0.96 (0.69–1.33)	0.80	0.93 (0.66–1.32)	0.68	1.51 (0.35–6.52)	0.58	78.8
rs16930545	C>T	Intron	–	0.170	0.166	1.05 (0.81–1.35)	0.72	1.08 (0.81–1.43)	0.62	0.90 (0.38–2.12)	0.80	94.3
rs7972007	T>C	Intron	–	0.172	0.166	1.07 (0.83–1.38)	0.61	1.10 (0.83–1.46)	0.51	0.89 (0.38–2.11)	0.79	94.4
rs7972248	C>T	Intron	0.02	0.388	0.407	0.93 (0.76–1.13)	0.45	0.90 (0.69–1.19)	0.48	0.91 (0.62–1.34)	0.64	99.1
rs7969082	G>A	Intron	0.53	0.252	0.265	0.98 (0.79–1.21)	0.84	0.95 (0.73–1.24)	0.71	1.06 (0.63–1.79)	0.83	97.9
rs758612	A>C	Intron	0.61	0.200	0.187	1.13 (0.88–1.43)	0.34	1.14 (0.86–1.50)	0.37	1.23 (0.58–2.61)	0.58	95.9
rs11062694	T>C	Intron	0.03	0.191	0.193	0.96 (0.75–1.21)	0.70	0.93 (0.71–1.23)	0.61	1.06 (0.52–2.13)	0.88	96.0
rs11062697	C>A	Intron	0.10	0.283	0.267	1.06 (0.86–1.30)	0.58	1.08 (0.82–1.40)	0.59	1.08 (0.67–1.74)	0.74	98.3
rs11062708	A>C	Intron	–	0.060	0.068	0.95 (0.64–1.40)	0.78	1.00 (0.67–1.50)	1	–	–	61.6
rs10848873	A>C	Intron	0.53	0.075	0.093	0.82 (0.58–1.17)	0.28	0.85 (0.60–1.22)	0.39	–	–	68.3
rs11062709	G>A	Intron	–	0.176	0.178	0.98 (0.77–1.24)	0.84	0.97 (0.73–1.29)	0.86	0.95 (0.46–1.96)	0.89	95.0
rs12581198	G>A	Intron	–	0.459	0.447	1.02 (0.85–1.23)	0.83	1.06 (0.79–1.42)	0.69	0.99 (0.71–1.37)	0.94	99.2
rs10848876	T>C	Intron	–	0.480	0.493	0.94 (0.77–1.13)	0.50	1.12 (0.83–1.52)	0.46	0.74 (0.54–1.01)	0.06	99.2
rs3741938	T>C	Intron	0.0006	0.461	0.462	1.01 (0.83–1.22)	0.95	1.14 (0.85–1.53)	0.38	0.86 (0.62–1.20)	0.38	99.3
rs3759363	A>G	Intron	0.006	0.212	0.189	1.18 (0.93–1.51)	0.18	1.20 (0.91–1.59)	0.19	1.24 (0.57–2.70)	0.58	96.0
rs3759362	T>C	Intron	0.0005	0.466	0.469	1.00 (0.82–1.21)	0.97	1.06 (0.79–1.43)	0.70	0.92 (0.67–1.28)	0.63	99.3
rs11062713	C>T	Intron	–	0.266	0.240	1.18 (0.94–1.47)	0.15	1.19 (0.91–1.56)	0.20	1.35 (0.76–2.40)	0.31	97.7
rs12423006	T>C	Intron	–	0.406	0.400	1.01 (0.83–1.24)	0.89	1.11 (0.84–1.47)	0.47	0.88 (0.60–1.27)	0.48	99.3
rs4766138	G>A	Intron	0.02	0.198	0.226	0.84 (0.67–1.06)	0.14	0.96 (0.73–1.26)	0.74	0.33 (0.17–0.66)	0.002	95.2
rs7960599	A>G	Intron	–	0.108	0.102	1.09 (0.80–1.48)	0.59	1.03 (0.74–1.44)	0.84	3.64 (0.70–18.83)	0.12	83.8
rs2159404	T>C	Intron	–	0.473	0.460	1.03 (0.85–1.25)	0.76	1.04 (0.77–1.39)	0.81	1.04 (0.76–1.44)	0.79	99.2
rs876594	C>T	Intron	0.00002	0.362	0.373	0.96 (0.78–1.16)	0.64	1.03 (0.78–1.35)	0.85	0.79 (0.53–1.17)	0.23	99.1
rs4766139	C>T	Intron	0.03	0.205	0.234	0.84 (0.67–1.05)	0.13	0.98 (0.74–1.28)	0.86	0.30 (0.15–0.59)	0.0005	95.7
rs10848881	A>C	Intron	–	0.059	0.065	0.96 (0.65–1.41)	0.82	0.97 (0.64–1.45)	0.86	0.64 (0.06–7.10)	0.71	61.5
rs10774155	C>T	Intron	–	0.179	0.177	1.04 (0.81–1.33)	0.77	1.15 (0.87–1.52)	0.34	0.50 (0.22–1.13)	0.10	95.2
rs10774156	C>A	Intron	0.005	0.451	0.434	1.05 (0.87–1.28)	0.60	1.13 (0.84–1.50)	0.42	1.00 (0.71–1.40)	0.99	99.2
rs11614792	T>C	Intron	–	0.492	0.501	0.96 (0.80–1.17)	0.71	1.07 (0.79–1.46)	0.66	0.85 (0.62–1.16)	0.29	99.2
rs9669266	A>G	Intron	–	0.369	0.390	0.91 (0.75–1.10)	0.33	0.98 (0.75–1.29)	0.91	0.71 (0.48–1.04)	0.08	99.0
rs12581829	A>C	Intron	–	0.105	0.137	0.72 (0.54–0.96)	0.02	0.71 (0.51–0.97)	0.03	0.52 (0.20–1.36)	0.18	79.1
rs10774158	G>A	Intron	0.09	0.179	0.179	1.02 (0.80–1.31)	0.85	1.14 (0.86–1.52)	0.36	0.46 (0.20–1.04)	0.06	95.3
rs4766141	C>G	Intron	–	0.210	0.187	1.16 (0.91–1.47)	0.24	1.16 (0.88–1.53)	0.30	1.39 (0.68–2.87)	0.37	95.9
rs3782749	T>G	Intron	–	0.054	0.064	0.90 (0.60–1.34)	0.60	0.90 (0.59–1.37)	0.63	0.64 (0.06–7.08)	0.71	56.6
rs11062723	G>A	Intron	–	0.409	0.393	1.07 (0.88–1.30)	0.52	1.12 (0.85–1.48)	0.41	1.03 (0.71–1.48)	0.90	99.2
rs3825339	A>G	Intron	–	0.224	0.210	1.10 (0.88–1.39)	0.40	1.13 (0.86–1.48)	0.40	1.12 (0.59–2.12)	0.74	96.9
rs3741936	G>A	Intron	0.14	0.272	0.285	0.93 (0.75–1.15)	0.49	0.92 (0.70–1.20)	0.52	0.90 (0.53–1.53)	0.69	98.3
rs917602	G>A	Intron	0.28	0.264	0.253	1.05 (0.85–1.31)	0.63	1.11 (0.85–1.45)	0.44	0.92 (0.55–1.55)	0.75	98.1
rs7966000	A>G	Intron	–	0.136	0.156	0.82 (0.63–1.08)	0.16	0.81 (0.60–1.09)	0.16	0.76 (0.28–2.11)	0.60	88.8
rs7957814	G.A	Intron	0.15	0.111	0.113	0.98 (0.73–1.32)	0.89	0.97 (0.70–1.34)	0.85	1.14 (0.30–4.36)	0.84	85.5
rs6489480	A.G	Intron	–	0.111	0.114	0.97 (0.72–1.31)	0.84	0.96 (0.69–1.32)	0.79	1.14 (0.30–4.36)	0.84	85.2
rs3782745	A.C	Intron	–	0.053	0.045	1.17 (0.76–1.79)	0.48	1.10 (0.70–1.72)	0.68	–	–	55.7
rs7307502	A.G	Intron	–	0.176	0.176	0.97 (0.76–1.24)	0.82	0.94 (0.70–1.24)	0.65	1.23 (0.57–2.65)	0.61	95.1
rs3782744	G.A	Intron	0.44	0.479	0.464	1.09 (0.91–1.32)	0.34	0.98 (0.74–1.32)	0.91	1.33 (0.97–1.82)	0.08	99.2
rs7976970	A.G	Intron	0.14	0.115	0.115	1.00 (0.74–1.35)	0.99	0.99 (0.72–1.37)	0.97	1.14 (0.30–4.36)	0.84	86.7
rs16930578	G.A	Intron	0.11	0.083	0.077	1.07 (0.75–1.52)	0.72	1.10 (0.76–1.58)	0.62	0.42 (0.04–4.69)	0.48	74.7
rs758637	G.A	Intron	0.93	0.381	0.382	0.98 (0.81–1.18)	0.80	0.89 (0.68–1.17)	0.41	1.13 (0.78–1.63)	0.53	99.2
rs7137875	A.G	Intron	0.34	0.137	0.149	0.89 (0.68–1.16)	0.38	0.88 (0.66–1.19)	0.41	0.76 (0.28–2.11)	0.60	89.7
rs11062731	G.C	Intron	–	0.129	0.138	0.90 (0.68–1.20)	0.47	0.90 (0.66–1.22)	0.50	0.81 (0.27–2.50)	0.72	88.7
rs11062733	C.T	Intron	0.22	0.099	0.102	0.94 (0.68–1.29)	0.69	0.94 (0.68–1.32)	0.73	0.69 (0.11–4.31)	0.69	81.7
rs4765741	G.A	Intron	0.47	0.479	0.466	1.08 (0.90–1.30)	0.42	0.99 (0.74–1.32)	0.92	1.27 (0.93–1.74)	0.14	99.2
rs11830814	G.C	Intergenic	–	0.082	0.078	1.06 (0.74–1.50)	0.76	1.08 (0.75–1.56)	0.67	0.42 (0.04–4.69)	0.48	74.8
rs2159347	C.T	Intergenic	–	0.117	0.091	1.31 (0.96–1.78)	0.09	1.35 (0.97–1.88)	0.08	1.21 (0.31–4.65)	0.79	82.5
rs1029766	G.A	Intergenic	0.77	0.402	0.407	0.97 (0.80–1.17)	0.72	0.86 (0.65–1.13)	0.28	1.14 (0.80–1.62)	0.47	99.3
				Frequency
BL1_ht1				0.441	0.429	1.03 (0.85–1.25)	0.74	1.10 (0.82–1.46)	0.53	0.97 (0.69–1.37)	0.88	99.1
BL1_ht4				0.081	0.074	1.19 (0.82–1.72)	0.35	1.19 (0.82–1.72)	0.35	–	–	71.3
BL2_ht1				0.461	0.455	1.03 (0.85–1.25)	0.76	1.13 (0.85–1.52)	0.40	0.93 (0.67–1.30)	0.69	99.2
BL3_ht3				0.062	0.055	1.12 (0.75–1.66)	0.59	1.19 (0.78–1.82)	0.41	0.27 (0.03–2.68)	0.27	59.8
BL4_ht3				0.158	0.138	1.19 (0.91–1.56)	0.20	1.16 (0.86–1.56)	0.32	2.14 (0.72–6.34)	0.17	89.3
BL4_ht5				0.065	0.060	1.04 (0.71–1.54)	0.84	1.09 (0.72–1.63)	0.69	0.29 (0.03–3.29)	0.32	63.4
BL4_ht6				0.056	0.064	0.92 (0.62–1.38)	0.70	0.96 (0.63–1.44)	0.83	–	–	56.3
BL5_ht2				0.370	0.389	0.93 (0.76–1.13)	0.44	1.01 (0.77–1.33)	0.94	0.73 (0.49–1.07)	0.10	98.8
BL5_ht3				0.121	0.112	1.09 (0.81–1.47)	0.57	1.09 (0.80–1.50)	0.59	1.21 (0.33–4.40)	0.77	85.1
BL6_ht2				0.265	0.253	1.08 (0.87–1.35)	0.48	1.09 (0.84–1.43)	0.51	1.13 (0.62–2.05)	0.69	97.8
BL6_ht3				0.125	0.116	1.09 (0.82–1.46)	0.55	1.11 (0.81–1.53)	0.50	0.94 (0.27–3.23)	0.92	86.1
BL7_ht2				0.205	0.241	0.81 (0.65–1.02)	0.07	0.94 (0.72–1.24)	0.68	0.28 (0.14–0.55)	0.0002	93.6
BL7_ht4				0.123	0.115	1.08 (0.81–1.45)	0.60	1.10 (0.80–1.51)	0.55	0.94 (0.27–3.23)	0.92	85.9
BL8_ht1				0.467	0.466	1.02 (0.85–1.22)	0.85	0.91 (0.68–1.21)	0.51	1.18 (0.86–1.61)	0.31	99.3
BL10_ht2				0.341	0.356	0.92 (0.76–1.12)	0.41	0.83 (0.63–1.08)	0.16	1.09 (0.73–1.64)	0.68	98.8
BL11_ht2				0.288	0.319	0.85 (0.69–1.04)	0.12	0.82 (0.63–1.06)	0.13	0.81 (0.51–1.30)	0.38	97.5

Notes: Boldface indicates P-value <0.05. P-values of GWAS represent the codominant model, which includes the additive model, adjusted for age and sex as covariates.

* P-value of logistic analysis under additive model by adjusting for sex and age as covariates.

Abbreviations: AA, amino acid; AL, alcoholic subjects; GWAS, genome-wide association study; ht, haplotype; MAF, minor allele frequency; PRMT8, protein arginine methyltransferase.

Table S2 Association analysis of PRMT8 SNPs with the AUDIT score in all study subjects (n=914)

Category	Loci	C/C		C/R		R/R		P-value*
		N	AUDIT score	N	AUDIT score	N	AUDIT score
AUDIT all	rs4766138	572	18.77±11.79	296	18.20±11.81	46	12.65±12.10	0.01
	rs4766139	562	18.75±11.79	303	18.36±11.82	49	12.33±11.80	0.01
	rs12581829	711	18.81±11.76	183	16.34±12.01	19	16.21±13.06	0.008
Alcohol consumption	rs4766138	572	8.12±3.58	296	7.98±3.61	46	6.48±4.25	0.04
	rs4766139	562	8.12±3.58	303	8.01±3.61	49	6.43±4.13	0.03
	rs12581829	711	8.13±3.56	183	7.45±3.88	19	7.74±3.86	0.03
Alcohol dependence	rs4766138	572	4.31±4.10	296	4.21±4.02	46	2.74±3.87	0.08
	rs4766139	562	4.28±4.09	303	4.30±4.05	49	2.59±3.80	0.09
	rs12581829	711	4.30±4.08	183	3.83±4.03	19	3.53±4.36	0.09
Alcohol-related harm	rs4766138	572	6.34±5.22	296	6.02±5.21	46	3.43±4.96	0.005
	rs4766139	562	6.35±5.23	303	6.06±5.20	49	3.31±4.86	0.003
	rs12581829	711	6.38±5.23	183	5.07±5.11	19	4.95±5.71	0.001

Notes: C/C, C/R, and R/R mean major homozygote, heterozygote, and minor homozygote, respectively. AUDIT score is mean±SD.

* P-value of linear regression analysis under additive model by adjusting for sex and age as covariates. Boldface indicates P-value <0.05.

Abbreviations: AUDIT, Alcohol Use Disorders Identification Test; PRMT8, protein arginine methyltransferase.

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