Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual

Cousminer, Diana L.; Wagley, Yadav; Pippin, James A.; Elhakeem, Ahmed; Way, Gregory P.; Pahl, Matthew C.; McCormack, Shana E.; Chesi, Alessandra; Mitchell, Jonathan A.; Kindler, Joseph M.; Baird, Denis; Hartley, April; Howe, Laura; Kalkwarf, Heidi J.; Lappe, Joan M.; Lu, Sumei; Leonard, Michelle E.; Johnson, Matthew E.; Hakonarson, Hakon; Gilsanz, Vicente; Shepherd, John A.; Oberfield, Sharon E.; Greene, Casey S.; Kelly, Andrea; Lawlor, Deborah A.; Voight, Benjamin F.; Wells, Andrew D.; Zemel, Babette S.; Hankenson, Kurt D.; Grant, Struan F. A.

doi:10.1186/s13059-020-02207-9

Table 1 Genome-wide significant loci (signals 1–27) and suggestive loci (signals S1-S13) supported by multiple phenotypes or skeletal sites

From: Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual

Signal	SNP	Phenotype	Chr	Position	A1	A2	AF^a	Beta	SE	P	r^2b	Info^c	Nearest gene^f	Novel^g/ known	Suggestive in ALSPAC^h
1	rs2762826	TBLH BMC a-size	1	52,785,140	C	T	0.071	0.425	0.075	1.48 × 10^–8		1	ZFYVE9 [P]	Novel
	rs74944906	TBLH BMD a-size	1	52,779,069	G	T	0.948	− 0.438	0.089	8.91 × 10^–7	1	1
2	rs13407288	Femoral neck BMD a-size	2	28,611,855	G	T	0.805	0.271	0.049	3.76 × 10^–8		0.849	FOSL2	Novel
	rs13407288	Femoral neck BMD b-timing	2	28,611,855	G	T	0.805	0.243	0.049	8.08 × 10^–7		0.849
3	rs78996674	Total hip BMC c-velocity	3	71,412,084	T	C	0.941	− 0.469	0.082	1.36 × 10^–8		0.988	FOXP1	Novel
4	rs10804749	Femoral neck BMC a-size	3	99,179,665	T	G	0.808	− 0.267	0.049	4.57 × 10^–8		0.998	MIR548G,	Novel
	rs73138342	Femoral neck BMC c-velocity	3	99,157,560	C	T	0.847	− 0.271	0.053	3.43 × 10^–7	0.92	0.987	COL8A1 [P]
	rs4453878	Femoral neck BMD a-size	3	99,170,409	C	T	0.819	− 0.251	0.050	6.64 × 10^–7	1	0.998
5	rs4591452	Total hip BMC c-velocity	3	149,208,719	C	T	0.893	0.352	0.060	6.73 × 10^–9		0.99	TM4SF4	Novel
	rs72615628	Total hip BMD c-velocity	3	149,210,256	A	G	0.893	0.328	0.060	5.29 × 10^–8	1	0.99
6	rs78543504	Total hip BMD b-timing	4	3,699,405	A	T	0.911	0.385	0.068	2.29 × 10^–8		0.881	ADRA2C	Novel
	rs78543504	Total hip BMD c-velocity	4	3,699,405	A	T	0.911	0.385	0.068	2.29 × 10^–8		0.881
	rs4916624	Total hip BMC c-velocity	4	3,691,543	A	T	0.927	0.368	0.072	3.84 × 10^–7	0.97	0.882
7	rs202099172	Distal 1/3 radius BMC b-timing	5	28,308,653	ATAT	A	0.926	0.420	0.074	1.44 × 10^–8		0.865	CDH9	Novel
	rs202099172	Distal 1/3 radius BMD b-timing	5	28,308,653	ATAT	A	0.926	0.348	0.071	9.39 × 10^–7		0.865
8	rs11751016	Distal 1/3 radius BMD c-velocity	6	52,017,180	G	A	0.708	− 0.228	0.042	4.76 × 10^–8		0.99	MIR133B, IL17A [P]	Novel
9	rs77977968	TBLH BMC c-velocity	7	139,335,659	C	T	0.948	0.510	0.088	9.34 × 10^–9		0.952	HIPK2	Novel
10	rs60380629	TBLH BMD c-velocity	7	151,694,110	C	T	0.935	0.454	0.078	8.18 × 10^–9		0.979	GALNTL5	Novel
	rs60380629	Total hip BMD b-timing	7	151,694,110	C	T	0.935	0.430	0.077	2.64 × 10–⁸		0.979
	rs79289671	Total hip BMD c-velocity	7	151,692,941	C	T	0.930	0.400	0.075	9.93 × 10^–8	0.99	0.97
11	rs7860141	Spine BMC c-velocity	9	32,137,832	G	C	0.816	− 0.282	0.051	4.87 × 10^–8		0.999	ACO1	Novel	y
12	rs1331428	TBLH BMD c-velocity	9	137,835,202	C	T	0.483	− 0.221	0.039	2.49 × 10^–8		0.988	FCN1	Novel
	rs4841948	Total hip BMD c-velocity	9	137,831,521	T	C	0.560	− 0.204	0.039	1.30 × 10^–7	0.82	0.997
13	rs56015205	Spine BMD b-timing	10	3,142,278	A	T	0.573	− 0.245	0.044	3.24 × 10^–8		0.868	PFKP	Novel
	rs56015205	Spine BMC b-timing	10	3,142,278	A	T	0.573	− 0.225	0.044	4.36 × 10^–7		0.868
14	rs11002218	Total hip BMC c-velocity	10	79,365,309	T	C	0.939	− 0.491	0.088	3.34 × 10^–8		0.997	KCNMA1	Known
	rs11002218	TBLH BMC c-velocity	10	79,365,309	T	C	0.939	− 0.451	0.089	4.94 × 10^–7		0.997
15	rs67416120	Femoral neck BMD b-timing	10	98,010,202	AAGAG	A	0.292	− 0.271	0.048	2.22 × 10^–8		0.955	BLNK	Novel
16	rs17140801	Femoral neck BMC c-velocity	16	6,680,114	C	T	0.868	0.319	0.055	9.99 × 10^–9		0.964	RBFOX1	Known
17	16:75655176	Distal 1/3 radius BMD b-timing	16	75,655,176	C	I	0.912	0.386	0.069	3.19 × 10^–8		0.849	TERF2IP [P]	Novel	y
	rs78580335	Femoral neck BMC b-timing	16	75,787,356	T	C	0.880	0.305	0.054	1.59 × 10^–8	0.48	0.971
18	rs1719484	Spine BMC a-size	17	72,547,434	C	G	0.853	− 0.297	0.054	3.80 × 10^–8		0.993	CD300C	Novel
19	rs72631380	Total hip BMC a-size	17	73,102,584	G	T	0.948	0.428	0.077	3.91 × 10^–8		0.952	SLC16A5	Novel
	rs72631380	Femoral neck BMC a-size	17	73,102,584	G	T	0.948	0.420	0.077	7.24 × 10^–8		0.952
20	rs10415015	Distal 1/3 radius BMC b-timing	19	4,818,488	C	G	0.897	− 0.351	0.063	2.70 × 10^–8		0.993	TICAM1	Novel
21	rs116463118	Skull BMD b-timing	19	41,648,588	C	T	0.939	− 0.527	0.095	3.47 × 10^–8		0.825	CYP2F1	Known
22^e	rs8130725	TBLH BMD b-timing	21	16,458,656	G	C	0.929	0.397	0.071	3.17 × 10^–8		0.939	NRIP1	Novel
23^e	rs9974832	Distal 1/3 radius BMD a-size	21	16,524,340	C	T	0.902	− 0.359	0.064	1.98 × 10^–8		0.997	NRIP1	Novel
24	rs72630065	Femoral neck BMC b-timing	23	72,080,371	C	G	0.914	0.292	0.053	4.15 × 10^–8		0.98	DMRTC1	Novel
25	X:75657132	Femoral neck BMC b-timing	23	75,657,132	C	T	0.939	0.521	0.088	4.74 × 10^–9		0.631	SMARCA2	Novel
	X:75657132	Femoral neck BMC a-size	23	75,657,132	C	T	0.939	0.504	0.087	8.47 × 10^–9		0.631
	X:75657132	Femoral neck BMD a-size	23	75,657,132	C	T	0.939	0.475	0.083	1.46 × 10^–8		0.631
26	X:76607583	Femoral neck BMC a-size	23	76,607,583	A	G	0.073	− 0.353	0.057	1.01 × 10^–9		0.952	FGF16	Novel
	rs201392388	Femoral neck BMC a-size	23	76,607,584	G	A	0.073	− 0.353	0.057	1.01 × 10^–9		0.952
	X:76607583	Total hip BMD a-size	23	76,607,583	A	G	0.073	− 0.325	0.058	2.06 × 10^–8		0.952
	rs201392388	Total hip BMD a-size	23	76,607,584	G	A	0.073	− 0.325	0.058	2.06 × 10^–8		0.952
27	rs144238538	Femoral neck BMC a-size	23	78,179,955	C	T	0.911	0.291	0.052	3.03 × 10^–8		0.981	P2RY10,	Novel
	rs144238538	Total hip BMD a-size	23	78,179,955	C	T	0.911	0.287	0.052	4.75 × 10^–8		0.981	MIR4328
	rs7050494	Spine BMC b-timing	23	78,094,413	G	T	0.897	0.271	0.049	4.97 × 10^–8	0.55	0.978
S1	rs17336942	TBLH BMD a-size	2	212,861,073	T	C	0.581	0.195	0.038	3.74 × 10^–7		0.996	ERBB4	Novel
	rs17336942	Total hip BMD a-size	2	212,861,073	T	C	0.581	0.190	0.038	8.38 × 10^–7		0.996
	rs17336942	Total hip BMC a-size	2	212,861,073	T	C	0.581	0.191	0.038	6.64 × 10^–7		0.996
S2	rs77349060	Spine BMC c-velocity	2	240,273,229	C	T	0.871	0.275	0.052	1.93 × 10^–7		0.996	HDAC4	Novel
	rs4852055	Total hip BMC c-velocity	2	240,281,878	A	G	0.848	0.250	0.048	2.10 × 10^–7	0.83	0.997
S3	rs56883672	Femoral neck BMC c-velocity	4	106,026,989	C	G	0.595	0.208	0.038	7.12 × 10^–8		0.999	TET2 [P]	Known
	rs6533178	Total hip BMC c-velocity	4	106,039,826	T	C	0.592	− 0.203	0.040	3.19 × 10^–7	0.43	0.965
S4	rs12641626	Femoral neck BMD a-size	4	169,760,004	G	A	0.912	0.357	0.067	1.27 × 10^–7		0.953	PALLD	Novel	y
	rs12641626	Femoral neck BMC a-size	4	169,760,004	G	A	0.912	0.348	0.067	2.36 × 10^–7		0.953
S5	rs79651589	TBLH BMC a-size	6	143,130,718	C	CTGTTTGTT	0.313	− 0.212	0.043	7.53 × 10^–7		0.79	HIVEP2	Novel
	rs79651589	Total hip BMC a-size	6	143,130,718	C	CTGTTTGTT	0.313	− 0.213	0.043	9.26 × 10^–7		0.79
S6	rs142924645	Total hip BMD b-timing	12	3,162,566	C	CT	0.943	− 0.425	0.085	7.02 × 10^–7		0.964	TEAD4	Novel
	rs185315462	Spine BMD b-timing	12	3,163,396	T	G	0.945	− 0.440	0.087	4.67 × 10^–7	1	0.964
S7	rs45554832	TBLH BMC a-size	14	30,375,005	C	T	0.930	− 0.400	0.075	1.09 × 10^–7		0.922	PRKD1	Novel
	rs45554832	Total hip BMD a-size	14	30,375,005	C	T	0.930	− 0.394	0.076	2.22 × 10^–7		0.922
	rs45554832	Femoral neck BMD a-size	14	30,375,005	C	T	0.930	− 0.413	0.076	6.07 × 10^–8		0.922
	rs45554832	Femoral neck BMC a-size	14	30,375,005	C	T	0.930	− 0.393	0.076	2.39 × 10^–7		0.922
	rs74040635	Total hip BMC a-size	14	30,388,192	T	C	0.943	− 0.449	0.085	1.36 × 10^–7	0.6	0.922
S8	rs9962766	TBLH BMC b-timing	18	71,009,151	G	A	0.894	− 0.306	0.062	7.92 × 10^–7		0.986	NETO1	Novel
	rs10622698	TBLH BMC a-size	18	71,025,487	A	ATT	0.862	− 0.290	0.056	2.58 × 10^–7	0.8	0.995
S9	rs77154151	TBLH BMC c-velocity	19	3,072,434	G	A	0.877	0.332	0.065	4.08 × 10^–7		0.795	AES	Novel	y
	rs12461372	Total hip BMC c-velocity	19	3,072,859	G	A	0.880	0.331	0.064	2.13 × 10^–7	0.99	0.796
S10	rs4283509	Femoral neck BMD c-velocity	21	23,031,423	C	A	0.882	0.292	0.057	3.79 × 10^–7		0.995	NCAM2	Novel
	21:23052938	Total hip BMC c-velocity	21	23,052,938	T	TG	0.268	− 0.237	0.047	5.62 × 10^–7	0.36	0.841
S11	rs2564086	Spine BMC a-size	2	5,944,498	C	T	0.274	0.225	0.045	5.21 × 10^–7		0.98	SOX11	Novel^d	y
S12	rs10866634	Distal 1/3 radius BMC a-size	5	168,748,968	T	G	0.145	0.268	0.054	9.14 × 10^–7		0.991	SLIT3	Novel^d
S13	rs11195210	Total hip BMC a-size	10	112,357,813	G	A	0.931	0.364	0.074	9.37 × 10^–7		0.979	SMC3	Known^d

^aAllele frequency in all samples (see ancestry-specific frequencies in Supplementary Table 6)
^bFor loci with more than one sentinel SNP, r² values are given between this SNP and that in the row above
^cInfo represents imputation quality
^dSuggestive association with heel eBMD (P < 10⁻⁴) in Morris et al. 2018
^eDespite their close physical proximity, signals 22 and 23 are not in LD (r² = 0.05)
^f[P] Genes implicated by promoter-interaction map
^gNot previously reported in GWAS of bone density
^hFull results presented in Supplementary Table 9. Y, nominal support

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