The Alzheimer Disease BIN1 Locus As a Modifier Ofgba-Associated Parkinson Disease

Supplementary data to:

The Alzheimer disease BIN1 locus as a modifier ofGBA-associated Parkinson disease

Table 1 with references

SNPs selected for analysis in mild and severe GBA mutation carriers

SNP / Annotated gene / Full name
(MIM#) / P value in
GWAS
(model) / Additional reason for selectiona
rs10949703 / PTPRN2 / Protein-tyrosine phosphatase, receptor-type, n, polypeptide 2 (601698) / 6.4x10-7
(Dominant) / May be active during early development of human brain(1).
rs7800486 / CACNA2D1 / Calcium channel, voltage-dependent, alpha-2/delta subunit 1
(114204) / 1.1x10-5
(Dominant) / Several roles in the nervous system and synapses(2).
rs13272940 / MCPH1 / Microcephalin 1
(607117) / 1.8x10-5
(Dominant) / Importance in human brain development(3).
rs11792219 / GADD45G / Growth arrest- and DNA damage-inducible gene GADD45, gamma
(604949) / 2.3x10-5
(Dominant) / Importance in human brain development(4).
rs6860670 / SV2C / Synaptic vesicle glycoprotein 2C
(610291) / 2.9x10-5
(Additive) / Associated with PD and smoking (5).
rs4263397 / BST1 / Bone marrow stromal cell antigen 1
(600387) / 1.1x10-4
(Dominant) / Associated with PD(6).
rs10898685 / RAB38 / Ras-associated protein rab38
(606281) / 1.9x10-4
(Dominant) / Family member of RAB7L1, a suspected PD gene(7).
rs13403026 / BIN1 / Bridging integrator 1 (601248) / 2.9x10-3
(Dominant) / Strongly associated with Alzheimer’s disease(8).

aReferences in supplementary data file

References

1.Abu-Amero KK, Kondkar AA, Salih MA et al. Partial chromosome 7 duplication with a phenotype mimicking the HOXA1 spectrum disorder. Ophthalmic Genet 2013: 34: 90-96.

2.Bauer CS, Tran-Van-Minh A, Kadurin I et al. A new look at calcium channel alpha2delta subunits. Curr Opin Neurobiol 2010: 20: 563-571.

3.Venkatesh T, Suresh PS. Emerging roles of MCPH1: Expedition from primary microcephaly to cancer. Eur J Cell Biol 2014.

4.Sultan FA, Sweatt JD. The role of the Gadd45 family in the nervous system: a focus on neurodevelopment, neuronal injury, and cognitive neuroepigenetics. Adv Exp Med Biol 2013: 793: 81-119.

5.Hill-Burns EM, Singh N, Ganguly P et al. A genetic basis for the variable effect of smoking/nicotine on Parkinson's disease. Pharmacogenomics J 2013: 13: 530-537.

6.Satake W, Nakabayashi Y, Mizuta I et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 2009: 41: 1303-1307.

7.Grill B, Bienvenut WV, Brown HM et al. C. elegans RPM-1 regulates axon termination and synaptogenesis through the Rab GEF GLO-4 and the Rab GTPase GLO-1. Neuron 2007: 55: 587-601.

8.Seshadri S, Fitzpatrick AL, Ikram MA et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 2010: 303: 1832-1840.

Supplementary table 1 – Top 20 SNPs from GWAS data associated with age at onset among 79 mild GBA mutation carriers, dominant and additive models.

dbSNPrs / Associated Gene / MAF / HWE P / AAO AA, yrs / AAO Aa, yrs / AAO aa, yrs / pvaluea
Dominant model
rs10949703 / PTPRN2 / 0.22 / 0.19 / 55.67 / 50.17 / 63.32 / 6.44E-07
rs17151725 / MAGI2 / 0.43 / 1.00 / 58.13 / 53.97 / 66.58 / 5.12E-06
rs6015310 / STX16 / 0.39 / 0.48 / 59.30 / 53.90 / 66.11 / 6.08E-06
rs12913847 / KLF13 / 0.21 / 0.50 / 51.50 / 52.38 / 63.11 / 9.75E-06
rs1342836 / RYR2 / 0.29 / 1.00 / 50.86 / 54.25 / 64.05 / 1.08E-05
rs7800486 / CACNA2D1 / 0.31 / 0.44 / 65.78 / 63.55 / 53.64 / 1.08E-05
rs489969 / RYR2 / 0.26 / 0.57 / 49.50 / 53.85 / 63.79 / 1.14E-05
rs974801 / TET2 / 0.39 / 0.48 / 63.71 / 62.82 / 52.45 / 1.15E-05
rs2285720 / TET2 / 0.39 / 0.48 / 63.71 / 62.82 / 52.45 / 1.15E-05
rs773566 / MAGI3 / 0.41 / 0.10 / 62.12 / 63.58 / 52.48 / 1.28E-05
rs4644991 / SOX11 / 0.27 / 0.40 / 56.43 / 52.32 / 63.50 / 1.4E-05
rs17094670 / HTR7 / 0.30 / 0.42 / 56.20 / 53.81 / 64.38 / 1.49E-05
rs13272940 / MCPH1 / 0.37 / 0.24 / 51.88 / 55.64 / 65.59 / 1.83E-05
rs17149372 / SNX2 / 0.13 / 1.00 / 60.00 / 49.33 / 61.77 / 1.91E-05
rs3766875 / RYR2 / 0.28 / 1.00 / 52.50 / 54.25 / 64.05 / 2.01E-05
rs17267523 / GPC6 / 0.18 / 1.00 / 61.00 / 50.92 / 62.45 / 2.06E-05
rs11792219 / GADD45G / 0.27 / 1.00 / 65.67 / 64.00 / 54.19 / 2.3E-05
rs1246940 / RPP40 / 0.40 / 0.64 / 49.73 / 56.78 / 65.89 / 2.32E-05
rs4329917 / PLCG2 / 0.47 / 0.37 / 62.00 / 61.77 / 50.30 / 2.46E-05
rs3804133 / LRRC16A / 0.13 / 1.00 / 46.00 / 50.63 / 61.80 / 3.14E-05
Additive model
rs6561137 / ENOX1 / 0.39 / 0.69 / 48.62 / 57.75 / 64.77 / 2.14E-06
rs1246940 / RPP40 / 0.40 / 0.46 / 49.73 / 56.78 / 65.89 / 2.46E-06
rs12154701 / ETV1 / 0.49 / 0.43 / 51.95 / 58.39 / 66.41 / 5.9E-06
rs17167582 / ETV1 / 0.49 / 0.43 / 51.95 / 58.39 / 66.41 / 5.9E-06
rs7787720 / ETV1 / 0.49 / 0.31 / 51.95 / 58.54 / 65.83 / 1.21E-05
rs489969 / RYR2 / 0.26 / 0.44 / 49.50 / 53.85 / 63.79 / 1.21E-05
rs17503497 / RPL5 / 0.16 / 0.99 / 38.50 / 52.81 / 61.93 / 1.44E-05
rs1342836 / RYR2 / 0.29 / 0.87 / 50.86 / 54.25 / 64.05 / 1.61E-05
rs7795991 / ETV1 / 0.46 / 0.61 / 52.11 / 57.76 / 65.79 / 2.41E-05
rs13272940 / MCPH1 / 0.37 / 0.20 / 51.88 / 55.64 / 65.59 / 2.45E-05
rs7236632 / RSL24D1 / 0.11 / 0.92 / 30.00 / 51.13 / 61.22 / 2.48E-05
rs4809647 / SULF2 / 0.20 / 0.98 / 43.00 / 53.88 / 62.31 / 2.66E-05
rs7800486 / CACNA2D1 / 0.31 / 0.46 / 65.78 / 63.55 / 53.64 / 2.94E-05
rs6860670 / SV2C / 0.49 / 0.73 / 51.17 / 59.07 / 65.55 / 2.94E-05
rs3804133 / LRRC16A / 0.13 / 0.70 / 46.00 / 50.63 / 61.80 / 3.38E-05
rs4268948 / SNAR-C1 / 0.22 / 0.57 / 71.67 / 63.90 / 55.02 / 3.53E-05
rs10178322 / SNAR-C1 / 0.22 / 0.57 / 71.67 / 63.90 / 55.02 / 3.53E-05
rs10520501 / MGC45800 / 0.44 / 0.11 / 64.68 / 61.31 / 52.25 / 3.71E-05
rs1380202 / BCL11B / 0.48 / 0.44 / 66.85 / 58.00 / 53.43 / 4.07E-05
rs1677891 / NAV3 / 0.09 / 0.35 / 48.87 / 61.27 / 4.58E-05

MAF, minor allele frequency; HWE, Hardy-Weinberg Equilibrium; AAO, age at onset; AA, homozygous for the major allele; Aa, heterozygous for the minor allele; aa, homozygous for the minor allele.

a Uncorrected p value