Figures and data in The genetic architecture of NAFLD among inbred strains of mice

Version of Record: July 7, 2015
Accepted Manuscript: June 12, 2015

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Simon T Hui

Brian W Parks

Elin Org

Frode Norheim

Nam Che

Calvin Pan

Lawrence W Castellani

Sarada Charugundla

Darwin L Dirks

Nikolaos Psychogios

Isaac Neuhaus

Robert E Gerszten

Todd Kirchgessner

Peter S Gargalovic

Aldons J Lusis

(2015)
The genetic architecture of NAFLD among inbred strains of mice

eLife 4:e05607.

https://doi.org/10.7554/eLife.05607
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Figures
Tables
Additional files

11 figures, 11 tables and 2 additional files

Figures

Figure 1

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Effects of genetic background on hepatic TG accumulation.

(A) Hepatic TG levels in male mice after 8 weeks of HF/HS feeding. Results are presented as mean + SD. (B–D) Correlation of hepatic TG with liver weight (B), hepatic total cholesterol (TC) (C), and …
https://doi.org/10.7554/eLife.05607.003

Figure 2

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Plasma ALT activities and immune cell marker expression among inbred and recombinant inbred strains of mice.

(A) Plasma alanine aminotransferase (ALT) activities in male mice after 8 weeks of HF/HS feeding. Results are presented as mean + SD. (B–D) Correlation of plasma ALT activities with hepatic …
https://doi.org/10.7554/eLife.05607.004

Figure 3

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Correlation of hepatic TG content with plasma metabolites and HOMA-IR.

(A–F) Correlation of hepatic TG with plasma TG (A), plasma cholesterol (B), plasma glycerol (C), plasma insulin (D), plasma glucose (E), and HOMA-IR (F). r, biweight midcorrelation; p, p-value.

https://doi.org/10.7554/eLife.05607.005

Figure 4

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Correlation of hepatic TG content with adiposity and fat mass.

(A–E) Correlation of hepatic TG with adiposity (A), subcutaneous fat (B), gonadal fat (C), mesenteric fat (D), and retroperitoneal fat (E). r, biweight midcorrelation; p, p-value.

https://doi.org/10.7554/eLife.05607.006

Figure 5

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Association mapping of hepatic TG.

(A) Manhattan plot showing the significance (−log of p) of all SNPs and hepatic TG. Genome-wide significance cut-off at 1% false discovery rate (FDR) is shown by the red line and cut-off at 5% FDR …
https://doi.org/10.7554/eLife.05607.012

Figure 6

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Association mapping of hepatic TG with adiposity or insulin resistance as covariates.

Manhattan plot showing the significance −log₁₀ (p value) of all SNPs and hepatic TG conditioned for percentage body fat (A) or HOMA-IR (B) as covariates. Genome-wide significance cut-off at 1% FDR …
https://doi.org/10.7554/eLife.05607.013

Figure 7

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Correlation of candidate gene expression with hepatic TG content.

(A–B) Correlation of hepatic TG with expression levels of *Gde1* (A) and *Knop1* (B) in the liver. (C) Correlation of hepatic TG with expression levels of *Gde1* in the white adipose tissue. r, biweight …
https://doi.org/10.7554/eLife.05607.017

Figure 8

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Effects of *Gde1* overexpression in mice by adenoviral transduction.

C57BL/6 mice were injected with Ad-Gde1 (1 × 10⁹ pfu per mouse, *i.v.*) and fed with a HF/HS diet for 7 days. Control group received the same dose of Ad-LacZ. (A) Western-blot of liver homogenate …
https://doi.org/10.7554/eLife.05607.019

Figure 9

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Effects of *Gde1* knockdown in mice by adenoviral transduction.

C57BL/6 mice were injected with Ad-shGde1 (1 × 10⁹ pfu per mouse, *i.v.*) and fed with a HF/HS diet for 7 days. Control group received the same dose of Ad-Ctl. (A) Equal amounts of liver protein were …
https://doi.org/10.7554/eLife.05607.020

Figure 10

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Correlation of hepatic TG and polar metabolites in the plasma.

Correlation of hepatic TG with plasma levels of arginine (A), ornithine (B), citrulline (C), TMANO (D), creatine (E), and creatinine (F). r, biweight midcorrelation; p, p-value.

https://doi.org/10.7554/eLife.05607.021

Author response image 1

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Variation in candidate gene expression among strains.

The expression level of *Gde1* (A), *Knop1* (B) and *Coq7* (C) among HMDP strains are shown. Results are presented as mean ± SD in log2 scale.

https://doi.org/10.7554/eLife.05607.028

Tables

Table 1

Top 50 liver genes correlated with hepatic TG levels

https://doi.org/10.7554/eLife.05607.007

Rank	Gene symbol	r	P
1	Cd36	0.695	1.85E-17
2	Mrpl16	0.622	2.57E-13
3	Enc1	0.611	8.12E-13
4	2010003K11Rik	0.600	2.84E-12
5	Tceal8	0.599	3.00E-12
6	Cmpk1	0.598	3.32E-12
7	Avpr1a	−0.595	4.45E-12
8	Hmgcl	0.590	7.60E-12
9	Akap2	0.581	1.86E-11
10	C1ra	−0.572	4.34E-11
11	Reep3	0.562	1.16E-10
12	Skp1a	0.554	2.33E-10
13	Esd	0.551	3.11E-10
14	Hadh	0.550	3.48E-10
15	Syap1	0.549	3.66E-10
16	Ermp1	0.545	5.44E-10
17	Ang	−0.544	5.53E-10
18	Dak	0.543	6.24E-10
19	Matr3	−0.541	7.12E-10
20	Nudt9	0.538	9.35E-10
21	Srsf5	−0.538	9.89E-10
22	Vps29	0.537	1.04E-09
23	Ttc23	0.537	1.05E-09
24	Entpd5	0.536	1.14E-09
25	Chchd6	0.535	1.27E-09
26	Plekha1	0.534	1.32E-09
27	Mogat1	0.531	1.76E-09
28	S100a10	0.528	2.11E-09
29	Plin4	0.527	2.36E-09
30	Anxa2	0.525	2.73E-09
31	Srxn1	0.524	2.96E-09
32	Cstb	0.523	3.36E-09
33	Cml1	−0.522	3.70E-09
34	Tpp1	0.521	4.00E-09
35	Apoc2	0.518	5.06E-09
36	F7	−0.515	6.32E-09
37	Wfdc2	0.514	6.72E-09
38	Bche	0.514	6.72E-09
39	Mms19	−0.514	6.74E-09
40	Jun	0.513	7.05E-09
41	Lifr	−0.513	7.33E-09
42	Gjb1	−0.512	7.63E-09
43	Fabp2	0.511	8.56E-09
44	Morc4	0.510	9.22E-09
45	Rnf11	0.510	9.33E-09
46	Egfr	−0.509	1.03E-08
47	Slc16a7	0.507	1.12E-08
48	Gfm1	0.505	1.32E-08
49	Chpt1	0.505	1.33E-08
50	Rbbp4	−0.505	1.33E-08

Table 2

Top 50 adipose genes correlated with hepatic TG levels

https://doi.org/10.7554/eLife.05607.008

Rank	Gene symbol	r	p
1	Nrbp2	−0.624	2.42E-13
2	Cp	−0.598	4.15E-12
3	Hoxa7	−0.591	8.42E-12
4	Prkcb	0.585	1.62E-11
5	Cstb	0.582	2.03E-11
6	Cd53	0.582	2.06E-11
7	Smap2	0.580	2.62E-11
8	Sft2d1	0.578	3.04E-11
9	Btk	0.576	3.56E-11
10	Was	0.576	3.62E-11
11	Il7r	0.575	3.94E-11
12	Tmem53	−0.573	4.77E-11
13	Rgs10	0.572	5.70E-11
14	Srp19	0.571	6.27E-11
15	Gpc3	−0.570	6.53E-11
16	Bcl10	0.570	6.72E-11
17	Gpr65	0.570	6.82E-11
18	Tlr7	0.569	7.18E-11
19	Efhd2	0.569	7.26E-11
20	Actr3	0.568	7.77E-11
21	Cd72	0.568	8.02E-11
22	Dera	0.567	8.89E-11
23	Pip4k2a	0.566	9.63E-11
24	Hcst	0.566	9.64E-11
25	Tyms	0.566	9.78E-11
26	Cenpv	−0.566	9.79E-11
27	Plxnc1	0.565	1.05E-10
28	Birc5	0.565	1.07E-10
29	Ptpn18	0.563	1.27E-10
30	Hoxa5	−0.562	1.37E-10
31	Fam105a	0.562	1.43E-10
32	Capza1	0.562	1.44E-10
33	Nap1l3	−0.561	1.50E-10
34	Rgs18	0.561	1.51E-10
35	Phtf2	0.560	1.59E-10
36	Nckap1l	0.560	1.65E-10
37	Coro1c	0.560	1.67E-10
38	Coro1a	0.559	1.78E-10
39	Lrrfip1	0.559	1.89E-10
40	C1qb	0.557	2.13E-10
41	Taok3	0.556	2.28E-10
42	Ms4a6c	0.556	2.29E-10
43	Bco2	−0.556	2.33E-10
44	Adrb3	−0.556	2.34E-10
45	Arhgap9	0.556	2.37E-10
46	Lrmp	0.556	2.47E-10
47	Fyb	0.555	2.50E-10
48	Lipa	0.555	2.63E-10
49	Cdt1	0.555	2.65E-10
50	S100a4	0.554	2.80E-10

Table 3

Pathway-enrichment analysis of the top 1000 hepatic genes correlated with hepatic TG levels, assessed with the DAVID database, and presented as total genes meeting that criterion in each pathway …

https://doi.org/10.7554/eLife.05607.009

Category	Term	Count	Adj. p	Fold enrichment
GOTERM_CC_FAT	GO:0005739 ∼ mitochondrion	127	1.99E-05	1.57
KEGG_PATHWAY	mmu04610:Complement and coagulation cascades	18	3.93E-03	3.03
GOTERM_CC_FAT	GO:0044420 ∼ extracellular matrix part	17	5.89E-03	2.91

Table 4

Pathway-enrichment analysis of the top 1000 adipose genes correlated with hepatic TG levels, assessed with the DAVID database, and presented as total genes meeting that criterion in each pathway …

https://doi.org/10.7554/eLife.05607.010

Category	Term	Count	Adj. p	Fold enrichment
GOTERM_BP_FAT	GO:0000087 ∼ M phase of mitotic cell cycle	36	9.69E-06	2.87
KEGG_PATHWAY	mmu04142:Lysosome	25	1.73E-03	2.50
GOTERM_BP_FAT	GO:0008064 ∼ regulation of actin polymerization or depolymerization	19	5.97E-06	5.43
GOTERM_BP_FAT	GO:0007010 ∼ cytoskeleton organization	39	1.89E-02	1.87
GOTERM_BP_FAT	GO:0006955 ∼ immune response	50	1.80E-02	1.72
GOTERM_BP_FAT	GO:0009611 ∼ response to wounding	42	2.64E-02	1.78
GOTERM_BP_FAT	GO:0045321 ∼ leukocyte activation	34	7.64E-04	2.36
KEGG_PATHWAY	mmu04662:B cell receptor signaling pathway	20	8.62E-04	3.08
GOTERM_BP_FAT	GO:0001819 ∼ positive regulation of cytokine production	13	1.85E-02	3.56

Table 5

Correlation between human GWAS candidate gene expression in mouse liver and adipose tissue with hepatic TG level

https://doi.org/10.7554/eLife.05607.011

	Liver		Adipose
	r	p	r	p
Pnpla3	0.07	0.423	−0.04	0.645
Gckr	0.19	0.044*	0.14	0.156
Ncan	−0.10	0.316	0.37	6.1 × 10-5*
Tm6sf2	0.15	0.123	−0.23	0.012*
Lyplal1	0.27	0.003*	−0.12	0.228
Trib1	−0.10	0.313	0.24	0.012*

*

Denotes p < 0.05.

Table 6

Association p-values of candidate genes on chromosome 7 with the peak SNP for hepatic triglyceride levels

https://doi.org/10.7554/eLife.05607.014

Gene	Liver p-value	Liver expression	Adipose p-value	Adipose expression
Rps15a	NA	Yes	NA	Yes
Arl6ip1	0.011	Yes	0.294	Yes
Smg1	NA	No	NA	Yes
4930583K01Rik	NA	No	NA	Yes
Syt7	0.495	No	0.748	Yes
Itpripl2	NA	Yes	NA	Yes
Coq7	7.18E-13	Yes	7.96E-14	Yes
Tmc7	NA	Yes	NA	Yes
Tmc5	NA	No	NA	Yes
Gde1	3.21E-05	Yes	3.98E-08	Yes
Ccp110	NA	No	NA	No
9030624J02Rik	NA	Yes	NA	Yes
Knop1	3.85E-07	Yes	0.043	Yes
Iqck	NA	No	NA	No
Gprc5b	0.002	No	0.661	Yes
Gpr139	NA	Yes	NA	No
Gp2	0.910	No	0.209	No

Table 7

Candidate genes under the chromosomes 3, 9, and 11 loci

https://doi.org/10.7554/eLife.05607.015

Chromosome 3	Chromosome 9	Chromosome 11
1110032F04Rik	Nphp3	Il12b
Ift80	Uba5	Ublcp1
Smc4	Acad11	Rnf145
Trim59	Dnajc3	Ebf1
Kpna4	Acpp	Gm12159
Gm1647	Cpne4	F630206G17Rik
Arl14	Mrpl3	Clint1
Ppm1l	Nudt16	Lsm11
B3galnt1	1700080E11Rik	Thg1l
Nmd3	Nek11	Sox30
Sptssb	Aste1	Adam19
Otol1	Atp2c1	Nipal4
	Pik3r4	Cyfip2
		Itk
		Fam71b

Table 8

Significant cis-eQTL at chromosome 7 locus

https://doi.org/10.7554/eLife.05607.016

Gene	Gene start position	SNP ID	Position	Liver p-value
Arl6ip1	118118891	rs30668041	118266969	2.79E-24
Coq7	118509659	rs32461510	118350009	5.01E-24
Gde1	118688545	rs32511419	119070521	1.32E-06
Knop1	118842237	rs32246745	119160823	1.18E-07

Gene	Gene start position	SNP ID	Position	Adipose p-value
Arl6ip1	118118891	rs30668041	118266969	1.14E-36
Coq7	118509659	rs32430851	117961092	1.65E-18
Gde1	118688545	rs31516425	118372786	2.53E-12
Knop1	118842237	rs32532370	119288974	3.47E-10
Gprc5b	118972040	rs48647926	118918455	3.70E-09

eQTL, expression Quantitative Trait Locus.

Table 9

Missense variants of candidate genes on chromosome 7

https://doi.org/10.7554/eLife.05607.018

Gene	Missense variants
Rps15a	None
Arl6ip1	None
Smg1	None
4930583K01Rik	None
Syt7	Q117R
Itpripl2	R204H, V240L, S420G
Coq7	A290G
Tmc7	C73S, T358S
Tmc5	M11V, Q42L, V82D, A119T, V139I, P179S, A243G, R258K, V448I, E737D
Gde1	None
Ccp110	R180K, I199V, N248S, A326V, A332T, P427T, S439P, S445P, F624S, G746S
9030624J02Rik	S3A, D23G, V122A, G175A, T660M
Knop1	I70M, V49A
Iqck	V49A, S148N
Gprc5b	None
Gpr139	None
Gp2	V79D, R483G

The effect of missense mutation was assessed by PROVEAN software. Neutral amino acid substitutions, which do not affect protein stability and function are shown in blue whereas deleterious mutations are labeled in red.

Table 10

Correlation between hepatic lipids and gut microbiota

https://doi.org/10.7554/eLife.05607.022

	TG	TC	UC	PL
Family:
Clostridiaceae	−0.133	0.035	0.116	0.052
Erysipelotrichaceae	0.138	0.005	−0.057	−0.016
Lachnospiraceae	0.066	−0.112	0.000	0.045
Mogibacteriaceae	0.033	−0.055	−0.092	−0.089
Peptostreptococcaceae	0.006	−0.019	−0.003	0.096
Rikenellaceae	0.002	0.142	0.125	−0.047
Ruminococcaceae	0.138	0.176	0.169	0.030
S24-7	−0.092	0.003	−0.111	−0.166
Genus:
02d06	−0.146	−0.062	−0.05	0.012
Adlercreutzia	0.014	0.001	0.133	0.084
Akkermansia	−0.031	0.029	0.080	0.074
Allobaculum	−0.083	−0.205*	−0.178	−0.009
Anaeroplasma	−0.019	−0.047	0.001	0.018
Bifidobacterium	−0.014	−0.082	−0.131	−0.084
Blautia	0.003	−0.217*	−0.244†	−0.183
Clostridium	−0.108	−0.063	−0.044	−0.008
Clostridium.1	0.081	0.044	−0.023	0.015
Coprobacillus	−0.008	−0.075	−0.138	−0.130
Coprococcus	−0.016	0.174	0.261†	0.212*
Dehalobacterium	0.086	0.070	0.066	0.070
Dorea	0.078	0.070	0.056	0.081
Lactobacillus	0.005	0.021	−0.012	−0.073
Lactococcus	0.085	0.001	0.048	0.065
Oscillospira	0.140	0.127	0.261†	0.206*
R.Gnavus	0.103	−0.024	−0.037	−0.016
Roseburia	0.063	−0.090	−0.132	−0.151
Ruminococcus	0.099	−0.131	−0.160	−0.218*
Sarcina	−0.109	0.035	0.067	0.014
SMB53	−0.012	−0.069	−0.029	0.052
Turicibacter	−0.035	0.016	0.019	0.013

TG: triglyceride; TC: total cholesterol; UC: unesterified cholesterol; PL: phospholipids.
*

Denotes FDR < 0.05.
†

Denotes FDR <0.01.

Table 11

Inbred and recombinant inbred strains used in this study

https://doi.org/10.7554/eLife.05607.023

Inbred strains		Recombinant inbred strains
Strain	n	Strain	n	Strain	n
129X1/SvJ	4	AXB10/PgnJ	3	BXD1/TyJ	3
A/J	4	AXB12/PgnJ	5	BXD11/TyJ	2
AKR/J	5	AXB13/PgnJ	5	BXD12/TyJ	5
BALB/cJ	5	AXB15/PgnJ	4	BXD13/TyJ	2
BTBR T<+> tf/J	4	AXB19/PgnJ	5	BXD14/TyJ	4
BUB/BnJ	5	AXB19a/PgJ	4	BXD15/TyJ	5
C3H/HeJ	4	AXB19b/PgJ	5	BXD16/TyJ	3
C57BL/6J	4	AXB2/PgnJ	3	BXD19/TyJ	4
C57BLKS/J	4	AXB5/PgnJ	4	BXD20/TyJ	7
C57L/J	5	AXB6/PgnJ	3	BXD21/TyJ	5
C58/J	4	AXB8/PgnJ	5	BXD24/TyJ	4
CBA/J	4	BXA1/PgnJ	3	BXD31/TyJ	2
CE/J	4	BXA11/PgnJ	4	BXD32/TyJ	5
DBA/2J	4	BXA12/PgnJ	4	BXD34/TyJ	4
FVB/NJ	5	BXA13/PgnJ	3	BXD36/TyJ	4
I/LnJ	5	BXA14/PgnJ	4	BXD38/TyJ	4
KK/HlJ	5	BXA16/PgnJ	3	BXD39/TyJ	4
LG/J	4	BXA2/PgnJ	5	BXD40/TyJ	7
MA/MyJ	4	BXA24/PgnJ	4	BXD43/RwwJ	5
NOD/ShiLtJ	2	BXA4/PgnJ	4	BXD44/RwwJ	4
NON/ShiLtJ	5	BXA7/PgnJ	6	BXD45/RwwJ	5
NZB/BlNJ	4	BXA8/PgnJ	4	BXD48/RwwJ	4
NZW/LacJ	1	BXH19/TyJ	6	BXD49/RwwJ	4
PL/J	6	BXH2/TyJ	3	BXD5/TyJ	5
RIIIS/J	4	BXH20/KccJ	3	BXD50/RwwJ	4
SEA/GnJ	4	BXH22/KccJ	4	BXD51/RwwJ	4
SJL/J	5	BXH4/TyJ	4	BXD55/RwwJ	4
SM/J	4	BXH6/TyJ	5	BXD56/RwwJ	6
SWR/J	4	BXH8/TyJ	3	BXD6/TyJ	5
		BXH9/TyJ	6	BXD60/RwwJ	2
		CXB11/HiAJ	5	BXD61/RwwJ	4
		CXB12/HiAJ	5	BXD62/RwwJ	6
		CXB13/HiAJ	5	BXD64/RwwJ	4
		CXB3/ByJ	5	BXD66/RwwJ	5
		CXB4/ByJ	5	BXD68/RwwJ	4
		CXB6/ByJ	6	BXD70/RwwJ	4
		CXB7/ByJ	6	BXD71/RwwJ	4
				BXD73/RwwJ	4
				BXD74/RwwJ	4
				BXD75/RwwJ	4
				BXD79/RwwJ	4
				BXD8/TyJ	2
				BXD84/RwwJ	4
				BXD85/RwwJ	4
				BXD86/RwwJ	5
				BXD87/RwwJ	3
				BXD9/TyJ	4