TABLE 1.
Listing of all found exonic and splice‐site variants, including specifications [Color table can be viewed at wileyonlinelibrary.com]
| Genotype information | Cohorts | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Position Chr 1 | cDNA | rsID | Exon | Protein | Allelic name | Clinical | PD patients | Control | OR | P |
| (GRCh37/hg19) | NM_000157.3 | NP_000148.2 | association | % (n) | % (n) | (95% CI) | ||||
| (n = 3402) | (n = 655) | |||||||||
| Heterozygous (simple and complex) | ||||||||||
| 155210876:C | c.26_27del | ‐ | 1 | p.(Glu9GlyfsTer8) | E‐30Gfs*8 | Novel | 0.0 (1) | 0 (0) | NA | NA |
| 155210492:G | c.44T > C | ‐ | 2 | p.(Leu15Ser) | L‐24S | Novel | 0.0 (1) | 0 (0) | NA | NA |
| 155210492:G | c.44T > C | ‐ | 2 | p.[(Leu15Ser;Ser16Gly)] | L‐24S + S‐23G | Novel | 0.0 (1) | 0 (0) | NA | NA |
| 155210490:C | c.46A > G | 2 | Novel | |||||||
| 155210441:C | c.95A > G | ‐ | 2 | p.(Gln32Arg) | Q‐7R | Novel | 0.0 (1) | 0 (0) | NA | NA |
| 155209813:T | c.171C > A | ‐ | 3 | p.(Cys57Ter) | C18* | Novel | 0.0 (1) | 0 (0) | NA | NA |
| 155209752:A | c.232C > T | rs146774384 | 3 | p.(Arg78Cys) | R39C | Novel | 0.0 (1) | 0 (0) | NA | NA |
| 155209732:AC | c.251_252insC | ‐ | 3 | p.(Ser84ArgfsTer15) | S45Rfs*15 | Novel | 0.0 (1) | 0 (0) | NA | NA |
| 155208421:A | c.475C > T | rs397515515 | 5 | p.(Arg159Trp) | R120W | GD | 0.1 (5) | 0 (0) | NA | NA |
| 155208361:G | c.535G > C | rs147138516 | 5 | p.[(Asp179His;Glu365Lys)] | D140H + E326K | GD | 2.4 (82) | 0.9 (6) | 2.7 | 0.012 |
| 155206167:T | c.1093G > A | rs2230288 | 8 | (1.2‐6.1) | ||||||
| 155208060:T | c.626G > A | ‐ | 6 | p.(Arg209His) | R170H | Novel | 0.0 (1) | 0 (0) | NA | NA |
| 155208001:T | c.685G > A | ‐ | 6 | p.(Ala229Thr) | A190T | GD | 0.0 (1) | 0 (0) | NA | NA |
| 155207965:T | c.721G > A | rs398123534 | 6 | p.(Gly241Arg) | G202R | GD | 0.0 (1) | 0 (0) | NA | NA |
| 155207367:T | c.764T > A | rs74500255 | 7 | p.(Phe255Tyr) | F216Y | GD | 0.0 (1) | 0 (0) | NA | NA |
| 155207266:T | c.865G > A | ‐ | 7 | p.(Gly289Ser) | G250S | Novel | 0.0 (1) | 0 (0) | NA | NA |
| 155207249:C | c.882T > G | rs367968666 | 7 | p.(His294Gln) | H255Q | GD | 0.1 (2) | 0 (0) | NA | NA |
| 155207235:G | c.896T > C | ‐ | 7 | p.(Ile299Thr) | I260T | GD | 0.1 (2) | 0 (0) | NA | NA |
| 155206172:G | c.1088T > C | ‐ | 8 | p.(Leu363Pro) | L324P | GD | 0.0 (1) | 0.2 (1) | 0.2 | 0.297 |
| (0.0–3.1) | ||||||||||
| 155206170:T | c.1090G > A | rs121908305 | 8 | p.(Gly364Arg) | G325R | GD | 0.0 (1) | 0 (0) | NA | NA |
| 155206167:T | c.1093G > A | rs2230288 | 8 | p.(Glu365Lys) | E326K | PD | 6.3 (213) | 2.6 (17) | 2.5 | <.001 |
| (1.5–4.1) | ||||||||||
| 155206158:A | c.1102C > T | rs374306700 | 8 | p.(Arg368Cys) | R329C | GD | 0.1 (2) | 0 (0) | NA | NA |
| 155206101:C | c.1159T > G | ‐ | 8 | p.(Trp387Gly) | W348G | GD | 0.0 (1) | 0 (0) | NA | NA |
| 155206093:G | c.1167G > C | ‐ | 8 | p.(Gln389His) | Q350H | Novel | 0.0 (1) | 0.2 (1) | 0.2 | 0.297 |
| (0.0–3.1) | ||||||||||
| 155206037:A | c.1223C > T | rs386626586 | 8 | p.(Thr408Met) | T369M | PD | 2.5 (86) | 1.8 (12) | 1.4 | 0.332 |
| (0.8–2.6) | ||||||||||
| 155205634:C | c.1226A > G | rs76763715 | 9 | p.(Asn409Ser) | N370S | GD | 0.9 (30) | 0.3 (2) | 2.9 | 0.151 |
| (0.7–12.2) | ||||||||||
| 155205619:C | c.1241T > G | ‐ | 9 | p.(Val414Gly) | V375G | Novel | 0.0 (1) | 0 (0) | NA | NA |
| 155205605:A | c.1255G > T | ‐ | 9 | p.(Asp419Tyr) | D380Y | GD | 0.0 (1) | 0 (0) | NA | NA |
| 155205581:T | c.1279G > A | rs149171124 | 9 | p.(Glu427Lys) | E388K | PD | 0.1 (3) | 0 (0) | NA | NA |
| 155205568:C | c.1292A > G | ‐ | 9 | p.(Asn431Ser) | N392S | PD | 0.0 (1) | 0 (0) | NA | NA |
| 155205518:G | c.1342G > C | rs1064651 | 9 | p.(Asp448His) | D409H | GD | 0.0 (1) | 0 (0) | NA | NA |
| 155205043:G | c.1448T > C | rs421016 | 10 | p.(Leu483Pro) | L444P | GD | 0.6 (21) | 0 (0) | NA | 0.037 |
| 155205016:A | c.[1475A > T; 1474G > C] | ‐ | 10 | p.(Asp492Leu) | D453L | Novel | 0.1 (4) | 0 (0) | NA | NA |
| 155205017:G | 10 | (D453V + D453H) | ||||||||
| 155204996:T | c.1495G > A | ‐ | 10 | p.(Val499Met) | V460M | GD | 0.0 (1) | 0 (0) | NA | NA |
| 155204986:G | c.1505G > C | ‐ | 10 | p.(Arg502Pro) | R463P | GD | 0.1 (2) | 0.2 (1) | 0.4 | 0.410 |
| (0.0–4.2) | ||||||||||
| 155204829:A | c.1568C > T | ‐ | 11 | p.(Ser523Leu) | S484L | Novel | 0.0 (1) | 0 (0) | NA | NA |
| 155204818:T | c.1579T > A | ‐ | 11 | p.(Ser527Thr) | S488T | PD | 0.0 (1) | 0 (0) | NA | NA |
| 155204811:C | c.1586A > G | ‐ | 11 | p.(His529Arg) | H490R | Novel | 0.0 (1) | 0 (0) | NA | NA |
| Likely recombinant alleles | ||||||||||
| 155207210:A, | c.924C > T, | — | 7 | p.(Leu307=), | L268=, S271G, D409H | Novel | 0.0 (1) | 0 (0) | NA | NA |
| 155207203:C, | c.931A > G, | — | 7 | p.(Ser310Gly), | ||||||
| 9 | ||||||||||
| 9 | D409H, L444P, A456P, V460=(a.k.a. RecTL) | GD | 0.0 (1) | 0 (0) | NA | NA | ||||
| 10 | ||||||||||
| 155205008:G, | c.1483G > C, | — | 10 | p.(Ala495Pro), | ||||||
| 10 | ||||||||||
| 10 | L444P, A456P, V460=(a.k.a. RecNcil) | GD | 0.1 (4) | 0 (0) | NA | NA | ||||
| 10 | ||||||||||
| 10 | ||||||||||
| Homozygous or compound heterozygous (variant details in listing above) | ||||||||||
| p.[(Leu363Pro)];[(Thr408Met)] | L324P / T369M | GD / PD | 0.0 (1) | 0 (0) | NA | NA | ||||
| p.[(Asp179His;Glu365Lys)]; [(Thr408Met)] | D140H + E326K / T369M | GD / PD | 0.0 (1) | 0 (0) | NA | NA | ||||
| p.[(Asp179His;Glu365Lys)]; [(Glu365Lys)] | D140H + E326K / E326K | GD / PD | 0.0 (1) | 0 (0) | NA | NA | ||||
| p.[(Glu365Lys)];[(Thr408Met)] | E326K / T369M | PD / PD | 0.1 (4) | 0 (0) | NA | NA | ||||
| p.[(Glu365Lys)];[(Glu365Lys)] | E326K / E326K | PD / PD | 0.2 (6) | 0 (0) | NA | NA | ||||
| p.[(Thr408Met)];[(Thr408Met)] | T369M / T369M | PD / PD | 0.0 (1) | 0 (0) | NA | NA | ||||
| Uncertain phasing (variant details in listing above) | ||||||||||
| 155210424:T, … | c.112T > A, … | —, … | 2, … | p.(Ser38Thr)(;)(Thr408Met) | S‐1T, T369M | Novel, PD | 0.0 (1) | 0 (0) | NA | NA |
| p.(Gln32Arg)(;)(Asn409Ser) | Q‐7R, N370S | Novel, GD | 0.0 (1) | 0 (0) | NA | NA | ||||
| p.[(Asp179His;Glu365Lys)](;)(Val498=) | D140H + E326K, V459= | GD, Syn | 0.0 (1) | 0 (0) | NA | NA | ||||
| …, 155204793:T | …, c.1604G > A | …, rs80356773 | …, 11 | p.[(Asp179His;Glu365Lys)](;)Arg535His) | D140H + E326K, R496H | GD, GD | 0.0 (1) | 0 (0) | NA | NA |
| p.(Arg209His)(;)(Glu365Lys) | R170H, E326K | Novel, PD | 0.0 (1) | 0 (0) | NA | NA | ||||
| p.[(Glu365Lys)];[(Thr408Met)](;)(Leu483Pro) | E326K / T369M, L444P | PD / PD, GD | 0.0 (1) | 0 (0) | NA | NA | ||||
| …, 155205574:T | …, c.1286G > A | …, ‐ | …, 9 | p.(Glu365Lys)(;)(Gly429Glu) | E326K, G390E | PD, Novel | 0.0 (1) | 0.2 (1) | 0.2 | 0.297 |
| (0.0–3.1) | ||||||||||
| p.(Glu365Lys)(;)(Val498=) | E326K, V459= | PD, Syn | 0.0 (1) | 0 (0) | NA | NA | ||||
| p.(Glu365Lys)(;)(Val499=) | E326K, V460= | PD, Syn | 0.0 (1) | 0 (0) | NA | NA | ||||
| p.(Thr408Met)(;)(Asp492Leu) | T369M, D453L | PD, Novel | 0.0 (1) | 0 (0) | NA | NA | ||||
| p.(Thr408Met)(;)(Leu483Pro) | T369M, L444P | PD, GD | 0.1 (3) | 0 (0) | NA | NA | ||||
| p.(Asn409Ser)(;)(Leu483Pro) | N370S, L444P | GD, GD | 0.0 (1) | 0 (0) | NA | NA | ||||
| Synonymous | ||||||||||
| 155209816:A | c.168C > T | rs145773486 | 3 | p.(Val56=) | V17= | Syn | 0 (0) | 0.2 (1) | NA | 0.161 |
| 155209684:T | c.300G > A | — | 3 | p.(Thr100=) | T61= | Syn | 0.0 (1) | 0 (0) | NA | NA |
| 155208422:A | c.474C > T | rs147411159 | 5 | p.(Ile158=) | I119= | Syn | 0.1 (5) | 0 (0) | NA | NA |
| 155208389:T | c.507C > A | — | 5 | p.(Ile169=) | I130= | Syn | 0.0 (1) | 0 (0) | NA | NA |
| 155208350:T | c.546G > A | — | 5 | p.(Gln182=) | Q143= | Syn | 0.0 (1) | 0 (0) | NA | NA |
| 155207990:T | c.696G > A | rs375731497 | 6 | p.(Gly232=) | G193= | Syn | 0.0 (1) | 0.2 (1) | 0.2 | 0.297 |
| (0.0‐3.1) | ||||||||||
| 155207984:A | c.702G > T | — | 6 | p.(Gly234=) | G195= | Syn | 0.0 (1) | 0 (0) | NA | NA |
| 155206111:A | c.1149C > T | — | 8 | p.(Gly383=) | G344= | Syn | 0.0 (1) | 0 (0) | NA | NA |
| 155206036:T | c.1224G > A | rs138498426 | 8 | p.(Thr408=) | T369= | Syn | 0.1 (2) | 0 (0) | NA | NA |
| 155205018:A | c.1473C > T | rs149257166 | 10 | p.(Pro491=) | P452= | Syn | 0.0 (1) | 0 (0) | NA | NA |
| 155204997:A | c.1494C > T | rs371779859 | 10 | p.(Val498=) | V459= | Syn | 0.1 (3) | 0 (0) | NA | NA |
| 155204994:G | c.1497G > C | rs1135675 | 10 | p.(Val499=) | V460= | Syn | 0.0 (1) | 0 (0) | NA | NA |
| Splice site (distance of 6 nucleotides or less) | ||||||||||
| 155207374:T | c.762‐5G > A | — | Intr. | — | — | Novel | 0.0 (1) | 0 (0) | NA | NA |
| 155206264:A | c.1000‐4G > T | — | Intr. | — | — | Novel | 0 (0) | 0.2 (1) | NA | 0.161 |
|
Exonic variants (details above) fulfilling splice‐site criteria (variant [distance]) — see Supplementary Table 4 for splicing prediction: p.E‐30Gfs*8 (1), p.S‐1T (4), p.F216Y (3), p.T369= (1), p.T369M (2), p.N370S (2), p.R463P (1) |
||||||||||
| Grouped comparisons | ||||||||||
| All Novel genotypes | 0.7 (23) | 0.3 (2) | 1.5 | 0.788 | ||||||
| (0.4–4.9) | ||||||||||
| All PD genotypes (p.E326K, p.T369M, p.E388K, p.S488T, p.N392S) | 9.3 (317) | 4.4 (29) | 2.2 | <0.001 | ||||||
| (1.5–3.3) | ||||||||||
| All GD genotypes | 5.0 (170) | 1.5 (10) | 3.4 | <0.001 | ||||||
| (1.8‐–6.5) | ||||||||||
| Total non‐synonymous | 15.0 (510) | 6.4 (42) | 2.6 | <0.001 | ||||||
| (1.9–3.6) | ||||||||||
GD, Gaucher's disease; PD, Parkinson's disease; syn, synonymous; NA, not applicable; Intr., intronic.
The sixth column “allelic name” contains the annotation historically used in Gaucher's disease literature, excluding the 39–amino acid signaling peptide. All genotype frequencies are compared with the abdominal aortic aneurysm control cohort, ORs are given with the 95% CIs and a P value. A P < 0.05 is given in boldface, and the rows of these genotypes are filled gray. OR could not be calculated if frequency was 0 in either group. If 6 cases or less were affected in patients and zero in controls, P value is set to NA. The coding (or sense) strand for GBA1 is the reverse strand of the DNA (as opposed to the forward strand). The chromosome position and nucleotide reflect the forward strand, whereas the cDNA annotation indicates the variant on the coding strand, which is in this case the reverse strand, and therefore these are complementary. Both intronic splice‐site variants were predicted not to affect splicing (see supplementary material) and were therefore not included in the overall analysis.