The inherited genetic contribution and polygenic risk score for risk of CLL and MBL: a narrative review

Figures & data

Figure 1. List of the first 10 SNPs found to be associated with CLL risk and the association with CLL and MBL risk across five studies. InterLymph CLL study by Berndt et al. including 4486 CLL and 13,183 controls (Black); AA CLL study by Kleinstern et al. including 173 AA CLL cases from the AA CLL cohort and 235 AA controls from the Mayo Clinic Biobank (red); MBL meta-analysis study by Crowther-Swanepoel et al. including 419 individuals with MBL and 1753 controls obtained from three sites (blue); GEC MBL study by Kleinstern et al. including 95 familial MBL individuals and 1,267 Mayo controls (blue); Mayo Clinic MBL study by Kleinstern et al. including 560 individuals with MBL from the Mayo Clinic and 2631 controls from the Mayo Clinic Biobank (blue); SNPs: single nucleotide polymorphisms; CLL: chronic lymphocytic leukemia; MBL: monoclonal B-cell lymphocytosis; InterLymph: International Lymphoma of Epidemiology Consortium; AA: African ancestry; GEC: genetic epidemiology of CLL Consortium; OR: odds ratio; CI: confidence interval.

Figure 2. List of additional 31 SNPs found to be associated with CLL risk and the association with CLL and MBL risk across four studies. InterLymph CLL study by Berndt et al. including 4,486 CLL and 13,183 controls (Black); AA CLL study by Kleinstern et al. including 173 AA CLL cases from the AA CLL cohort and 235 AA controls from the Mayo Clinic Biobank (red); GEC MBL study by Kleinstern et al. including 95 familial MBL individuals and 1267 Mayo controls (blue); Mayo Clinic MBL study by Kleinstern et al. including 560 individuals with MBL from the Mayo Clinic and 2631 controls from the Mayo Clinic Biobank (blue); SNPs: single nucleotide polymorphisms; CLL: chronic lymphocytic leukemia; MBL: monoclonal B-cell lymphocytosis; InterLymph: International Lymphoma of Epidemiology Consortium; AA: African ancestry; GEC: genetic epidemiology of CLL Consortium; OR: odds ratio; CI: confidence interval.

Table 1. List of 41 SNPs associated with CLL risk and their association with MBL risk across three studies.

Locus	Nearest gene(s)	Lead SNP in published fine mapping GWAS	Risk allele	Results from Law et al. Nat Commun (2017). Effect sizes from CLL GWAS used for the PRS calculations)		Results from Kleinstern et al. Blood (2018). Association between GEC MBL (n = 95) vs. Mayo controls (n = 1267)		Results from Kleinstern et al. Leukemia (2022). Mayo Clinic Study. Association between MBL (n = 560) vs. controls (n = 2631)		Results from Crowther et al. Blood (2010). Meta-analysis of three MBL studies totaling 419 MBLs vs. 1753 controls
				OR (95% CI)	p	OR (95% CI)	p	OR^§ (95% CI)	p	SNP	OR (95% CI)
1p36.11	MDS2	rs34676223	C	1.19 (1.14–1.25)	5.04E-13	1.29 (0.91–1.83)	0.15	1.09 (0.93–1.27)	0.29
1q42.13	RHOU	rs41271473	G	1.19 (1.13–1.26)	1.06E-10	0.98 (0.68-1.41)	0.9	0.97 (0.82-1.15)	0.72
2p22.2	QPCT, PRKD3	rs888096	A	1.15 (1.09–1.21)	5.20E-08	1.10 (0.81–1.50)	0.54	1.07 (0.93–1.23)	0.34
2q13	ACOXL, BCL2L11	rs1002015	C	1.30 (1.23–1.37)	2.23E-23	1.55 (1.12–2.15)	0.008	1.26 (1.10–1.45)	8.9 × 10^-4	rs17483466	1.27 (1.04–1.56)
		rs58055674	C	1.41 (1.32–1.5)	2.02E-27	1.32 (0.94–1.86)	0.11	1.26 (1.06–1.50)	0.01
		rs6708784	G	1.30 (1.24–1.37)	2.67E-25	1.14 (0.85–1.54)	0.39	1.15 (1.00–1.31)	0.05
2q33.1	CASP10/CASP8	rs7558911	A	1.18 (1.12–1.24)	5.05E-11	1.11 (0.82–1.49)	0.52	1.21 (1.05–1.38)	0.01
2q37.1	SP110, SP140	rs34004493	G	1.39 (1.31–1.47)	3.67E-32	1.44 (1.05–1.98)	0.03	1.45 (1.25–1.68)	1.1 × 10^-6	rs13397985	1.40 (1.13–1.72)
2q37.3	FARP2	rs757978	T	1.29 (1.2–1.39)	5.80E-11	1.45 (0.93–2.25)	0.1	1.17 (0.96–1.44)	0.12		1.38 (1.05-1.82)
3p24.1	EOMES	rs9880772	A	1.16 (1.11–1.22)	1.91E-09	1.02 (0.76–1.39)	0.88	1.00 (0.87–1.15)	0.98
3q26.2	MYNN, TERC	rs1317082	A	1.19 (1.12–1.26)	5.77E-09	1.24 (0.86–1.77)	0.25	1.24 (1.05–1.46)	0.01
4q24	BANK1	rs13107612*	C	1.17 (1.11–1.22)	1.37E-10	1.25 (0.89–1.76)	0.2	1.08 (0.93–1.26)	0.28
4q25	LEF1	rs7690934	C	1.16 (1.11–1.22)	6.08E-09	1.20 (0.88–1.65)	0.24	1.07 (0.93–1.23)	0.33
4q35.1	LOC728175	rs57214277	T	1.13 (1.08–1.18)	3.69E-08	0.99 (0.73–1.34)	0.96	1.17 (1.02–1.34)	0.02
5p15.33	TERT	rs7705526	A	1.18 (1.12–1.25)	5.90E-10	1.38 (1.02–1.87)	0.04	1.17 (1.02–1.35)	0.03
6p25.3	IRF4	rs9392504	A	1.33 (1.26–1.4)	9.81E-29	1.52 (1.12–2.07)	0.01	1.26 (1.10–1.44)	0.001	rs872071	1.27 (1.06–1.51)
6p21.32	HLA	rs9271176	G	1.29 (1.22–1.36)	3.16E-20	1.20 (0.86–1.66)	0.29	1.12 (0.96–1.30)	0.14
6p21.31	BAK1	rs210143	C	1.26 (1.19–1.33)	5.77E-16	1.07 (0.77–1.48)	0.7	1.03 (0.89–1.20)	0.69
6p21.31	C6orf106	rs3800461	C	1.20 (1.13–1.28)	1.97E-08	1.16 (0.74–1.82)	0.52	1.11 (0.90–1.37)	0.31
6q25.2	IPCEF1	rs4869818	G	1.15 (1.09–1.21)	4.11E-08	1.02 (0.76–1.37)	0.9	1.00 (0.88–1.15)	0.97
7q31.33	POT1	rs2267708	T	1.16 (1.1–1.22)	8.55E-09	1.33 (0.99–1.79)	0.06	1.26 (1.10–1.44)	0.001
8q22.3	ODF1	rs2511713	G	1.17 (1.1–1.23)	6.04E-08	1.03 (0.74–1.44)	0.84	1.30 (1.12–1.51)	0.001
8q24.21	POU5F1B	rs2466029	G	1.23 (1.17–1.3)	7.47E-16	1.12 (0.82–1.54)	0.47	1.15 (1.00–1.31)	0.05	rs2456449	1.31 (1.10–1.57)
9p21.3	CDKN2B-AS1	rs1679013	C	1.16 (1.1–1.22)	2.17E-08	1.17 (0.87–1.58)	0.3	1.16 (1.02–1.33)	0.03
10q23.31	ACTA, FAS	rs6586163	A	1.23 (1.17–1.29)	1.14E-15	1.27 (0.94–1.71)	0.13	1.22 (1.06–1.40)	0.004
11p15.5	C11orf21, TSPAN32	rs2651823	A	1.18 (1.13–1.25)	5.24E-11	1.16 (0.86–1.56)	0.33	1.02 (0.89–1.17)	0.81
11q23.2	TMPRSS5	rs61904987	T	1.24 (1.16–1.32)	2.46E-11	1.00 (0.64–1.58)	0.98	1.08 (0.88–1.32)	0.48
11q24.1	SCN3B, GRAMD1B	rs35923643	G	1.63 (1.53–1.72)	4.26E-58	1.73 (1.26–2.39)	0.001	1.48 (1.26–1.73)	9.1 × 10^-7	rs735665	1.63 (1.32–2.02)
12q24.13	OAS3	rs6489882	G	1.16 (1.1–1.22)	4.76E-08	1.24 (0.91–1.68)	0.17	1.14 (0.99–1.31)	0.07
15q15.1	BMF, BUB1B	rs8024033	C	1.26 (1.2–1.32)	7.13E-19	1.33 (0.98–1.80)	0.07	1.10 (0.96–1.26)	0.16
15q21.3	RFX7, NEDD4	rs142215530	G	1.39 (1.29–1.5)	2.46E-18	0.92 (0.57–1.49)	0.74	1.20 (0.97–1.48)	0.09	rs7169431	1.30 (0.95–1.77)
15q23	RPLP1	rs11637565	G	1.35 (1.28–1.42)	1.96E-31	1.50 (1.11–2.02)	0.008	1.22 (1.06–1.41)	0.01	rs7176508	1.18 (0.99–1.41)
16q24.1	IRF8	rs391855	A	1.34 (1.27–1.41)	1.25E-28	1.75 (1.25–2.44)	0.001	1.36 (1.18–1.56)	1.9 × 10^-5
		rs305065	C	1.16 (1.1–1.22)	7.57E-08	1.11 (0.82–1.52)	0.5	0.95 (0.82–1.10)	0.47	rs305061	1.16 (0.97–1.40)
18q21.1	CXXC1	rs1036935	A	1.15 (1.10–1.21)	3.27E-08	1.47 (1.07–2.04)	0.02	1.02 (0.87–1.20)	0.79
18q21.32	PMAIP1	rs4368253	C	1.17 (1.11–1.24)	1.26E-08	0.92 (0.70–1.27)	0.62	1.17 (1.01–1.35)	0.04
18q21.33	BCL2	rs77551289	A	1.37 (1.25–1.5)	1.83E-11	1.38 (0.76–2.52)	0.29	1.32 (1.03–1.69)	0.03
		rs4987852	C	1.32 (1.2–1.44)	4.66E-09	2.33 (1.47–3.67)	2.9 × 10^-4	1.32 (1.03–1.69)	0.03
19p13.3	ZBTB7A	rs7254272	A	1.17 (1.10–1.73)	4.67E-08	1.73 (1.22–2.46)	0.002	1.08 (0.90–1.29)	0.43
19q13.3	PRKD2, STRN4	rs874460	C	1.24 (1.15–1.34)	3.37E-08	1.18 (0.73–1.90)	0.49	1.12 (0.92–1.36)	0.27	rs11083846	0.99 (0.81–1.22)
22q13.33	NCAPH2	rs140522	T	1.15 (1.10–1.20)	2.70E-09	1.07 (0.78–1.47)	0.66	1.21 (1.05–1.40)	0.01

CLL: chronic lymphocytic leukemia; MBL: monoclonal B-cell lymphocytosis; GEC: genetic epidemiology of CLL Consortium; SNPs: single nucleotide polymorphisms; OR: odds ratio; CI: confidence interval; ^§adjusted for age, sex, and PC3; *Proxy for rs71597109.

Bold, statistically significant p < 0.05.

Figure 3. (A) Distribution of the CLL-PRS by controls and CLL/MBL cohorts from different studies. Boxplots representing the CLL-PRS distribution based on 41 CLL susceptibility SNPs, across controls (light grey), AA controls (dark grey), individuals with MBL (blue), CLL cases (red), and AA CLL cases (dark red). The horizontal line and score in each box represent the median CLL-PRS for each cohort. (B) Forest plot of the association between the CLL-PRS and risk of CLL and MBL across different studies. *InterLymph study by Kleinstern et al. including 8 studies from InterLymph with a CLL-PRS based on 41 CLL-susceptibility SNPs; **InterLymph study by Berndt et al. (in Press, Leukemia) including 24 studies from InterLymph with a CLL-PRS based on 43 CLL-susceptibility SNPs; PRS: polygenic risk score; SNPs, single nucleotide polymorphisms; CLL: chronic lymphocytic leukemia; MBL: monoclonal B-cell lymphocytosis; LC: low-count; HC: high-count; AA: African ancestry; InterLymph: International Lymphoma of Epidemiology Consortium; GEC: genetic epidemiology of CLL Consortium; FH: family history; OR: odds ratio; CI: confidence interval.

Table 2. Cohort and model description of the polygenic risk score studies.

Study	Cohort description	Independent cohorts	Analysis	Race	PRS c-stats (95% CI)	Number of SNPs in PRS	Adjustments/comments
Speedy et al. [28] 2014	CLL GWAS study	Participants were used to discover the CLL SNPs	CLL cases vs. controls	European	0.74	30	Unweighted PRS calculation; no adjustments
Kleinstern et al. [38] 2018	CLL GWAS study from InterLymph Consortium of 8 studies that had both GWAS and exposure data	Participants were used to discover the CLL SNPs	InterLymph CLL vs. InterLymph controls	European	0.79 (0.78–0.80)	41	Age, sex, ses, study
			FH^+ CLL vs. FH^+ controls	European	0.86 (0.82–0.90)	41	Age, sex, ses, study
			FH^- CLL vs. FH^- controls	European	0.79 (0.77–0.81)	41	Age, sex, ses, study
	GEC consortium study of CLL, MBL, and controls from CLL families and an additional set of Mayo controls agnostic to family history.	Independent cohorts	GEC CLL vs. GEC controls	European	0.80 (0.74–0.85)	41	Age, sex
			GEC CLL vs. Mayo controls	European	0.78 (0.74–0.81)	41	Age, sex
			GEC MBL vs. GEC controls	European	0.77 (0.70–0.85)	41	Age, sex
			GEC MBL vs. Mayo controls	European	0.77 (0.73–0.82)	41	Age, sex
Zhang et al. [41] 2020	InterLymph Consortium of 24 studies of CLL cases (N = 3100) and controls (N = 7667)	Participants were used to discover the CLL SNPs	InterLymph CLL vs. InterLymph controls	European	0.82 (se = 0.03)	2025	The c-stat represents the maximum c-stat theoretically achievable.
Berndt et al. [42] 2022	Mayo Clinic Study of CLL cases and controls	Independent cohorts	CLL cases vs. Mayo Clinic Biobank controls	European	0.77 (0.75–0.79)	41	Age, sex
	AA CLL cases and AA controls		AA CLL cases vs. AA controls	African	0.62 (0.57–0.68)	41	Age, sex
	MBLs screened from the Mayo Clinic Biobank, clinical MBL from the Mayo Clinic CLL Resource, and Mayo Clinic Biobank controls		Mayo MBL vs. Mayo Clinic Biobank controls	European	0.72 (0.69–0.73)	41	Age, sex
			Mayo LC-MBL vs. Mayo Clinic Biobank control	European	0.72 (0.70–0.75)	41	Age, sex
			Mayo HC-MBL vs. Mayo Clinic Biobank controls	European	0.73 (0.69–0.77)	41	Age, sex
Berndt et al. In Press Leukemia	InterLymph Consortium of CLL cases and controls from 24 studies	Participants were used to discover the CLL SNPs	InterLymph CLL vs. InterLymph controls	European	–	43	Age, sex, and principal components

CLL: chronic lymphocytic leukemia; MBL: monoclonal B-cell lymphocytosis; InterLymph: International Lymphoma of Epidemiology Consortium; AA: African ancestry; GEC: genetic epidemiology of CLL Consortium; FH: family history; PRS: polygenic risk score; SNPs: single nucleotide polymorphisms; CI: confidence interval; GWAS: genome-wide association study

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