rs56405341 Variant Associates with Expression of C4orf33 and C4orf33 Was Downregulated in Alzheimer's Disease and Progressive Supranuclear Palsy.

The first primary age-related tauopathy (PART) genome-wide association study confirmed significant associations of Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) genetic variants with PART, and highlighted a novel genetic variant rs56405341. Here, we perform a comprehensive analysis of rs56405341. We found that rs56405341 was significantly associated with C4orf33 mRNA expression, but not JADE1 mRNA expression in multiple brain tissues. C4orf33 was mainly expressed in cerebellar hemisphere and cerebellum, and JADE1 was mainly expressed in thyroid, and coronary artery. Meanwhile, we found significantly downregulated C4orf33 expression both AD and PSP compared with normal controls, respectively.

Causal association of genetically determined circulating vitamin D metabolites and calcium with multiple sclerosis in participants of European descent.

BACKGROUND: Vitamin D is an important regulator of calcium. Mendelian randomization (MR) studies exclusively focused on the circulating total 25-hydroxyvitamin D (25(OH)D) as a biomarker of vitamin D status, and have found the causal association between 25(OH)D and the risk of multiple sclerosis (MS). However, it currently remains unclear about the causal association of the 25(OH)D subtypes including 25(OH)D3 and C3-epi-25(OH)D3, as well as calcium with the risk of MS. METHODS: We performed a two-sample MR study to evaluate the causal association of circulating total 25(OH)D, 25(OH)D3, C3-epi-25(OH)D3, and calcium with the risk of MS using large-scale genome-wide association studies (GWAS) datasets from total 25(OH)D (n = 417,580), 25(OH)D3 (n = 40,562), C3-epi-25(OH)D3 (n = 40,562), calcium (n = 305,349), and MS (14,802 MS and 26,703 controls). We selected five MR methods including inverse-variance weighted (IVW), simple median, weighted median, MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier), and contamination mixture method. RESULTS: IVW showed that the genetically increased circulating 25(OH)D level (OR = 0.81, 95% CI: 0.70-0.94, P = 4.00E-03), circulating 25(OH)D3 level (OR = 0.85, 95% CI: 0.76-0.95, P = 5.00E-03), and circulating C3-epi-25(OH)D3 level (OR = 0.85, 95% CI: 0.74-0.98, P = 2.30E-02) were causally associated with reduced risk of MS. However, IVW showed no causal association between circulating calcium level and the risk of MS with OR = 2.85, 95% CI: 0.42-19.53, P = 2.85E-01. CONCLUSIONS: Our current findings together with evidence from other MR studies support the use of vitamin D but not calcium supplementation for the prevention of MS.

Evaluating the Bidirectional Causal Association Between Daytime Napping and Alzheimer's Disease Using Mendelian Randomization.

BACKGROUND: Until now, both cross-sectional and longitudinal studies have identified controversial findings about the association between daytime napping and Alzheimer's disease (AD) or cognitive decline. Therefore, it remains unclear about the causal association between daytime napping and AD or cognitive decline. OBJECTIVE: We aim to investigate the causal association between daytime napping and AD. METHODS: Here, we conduct a bidirectional Mendelian randomization (MR) analysis to investigate the causal association between daytime napping and AD using large-scale GWAS datasets from daytime napping including 452,633 individuals of European ancestry and AD including 35,274 AD and 59,163 controls of European ancestry. A total of five MR methods are selected including inverse-variance weighted (IVW), weighted median, MR-Egger, MR-PRESSO, and contamination mixture method. RESULTS: MR analysis highlights significant causal association of AD with daytime napping using IVW (beta = -0.006, 95% CI [-0.009, -0.002], p = 2.00E-03), but no significant causal association of daytime napping with AD using IVW (OR = 0.76, 95% CI 0.53-1.10, p = 1.40E-01). CONCLUSION: Our bidirectional MR analysis demonstrates the causal effect of AD on daytime napping. However, there is no causal effect of daytime napping on AD. Our current findings are consistent with recent evidence from other MR studies that highlight little evidence supporting a causal effect of sleep traits on AD and support the causal effect of AD on sleep traits.

Parkinson's Disease rs117896735 Variant Regulates INPP5F Expression in Brain Tissues and Increases Risk of Alzheimer's Disease.

BACKGROUND: Both INPP5D and INPP5F are members of INPP5 family. INPP5F rs117896735 variant was associated with Parkinson's disease (PD) risk, and INPP5D was an Alzheimer's disease (AD) risk gene. However, it remains unclear about the roles of INPP5F rs117896735 variant in AD. OBJECTIVE: We aim to investigate the roles of rs117896735 in AD. METHODS: First, we conducted a candidate variant study to evaluate the association of rs117896735 variant with AD risk using the large-scale AD GWAS dataset. Second, we conducted a gene expression analysis of INPP5F to investigate the expression difference of INPP5F in different human tissues using two large-scale gene expression datasets. Third, we conducted an expression quantitative trait loci analysis to evaluate whether rs117896735 variant regulate the expression of INPP5F. Fourth, we explore the potentially differential expression of INPP5F in AD and control using multiple AD-control gene expression datasets in human brain tissues and whole blood. RESULTS: We found that 1) rs117896735 A allele was associated with the increased risk of AD with OR = 1.15, 95% CI 1.005-1.315, p = 0.042; 2) rs117896735 A allele could increase INPP5F expression in multiple human tissues; 3) INPP5F showed different expression in different human tissues, especially in brain tissues; 4) INPP5F showed significant expression dysregulation in AD compared with controls in human brain tissues. CONCLUSION: Conclusion: We demonstrate that PD rs117896735 variant could regulate INPP5F expression in brain tissues and increase the risk of AD. These finding may provide important information about the role of rs117896735 in AD.

Cognitive performance protects against Alzheimer's disease independently of educational attainment and intelligence.

Mendelian-randomization (MR) studies using large-scale genome-wide association studies (GWAS) have identified causal association between educational attainment and Alzheimer's disease (AD). However, the underlying mechanisms are still required to be explored. Here, we conduct univariable and multivariable MR analyses using large-scale educational attainment, cognitive performance, intelligence and AD GWAS datasets. In stage 1, we found significant causal effects of educational attainment on cognitive performance (beta = 0.907, 95% confidence interval (CI): 0.884-0.930, P < 1.145E-299), and vice versa (beta = 0.571, 95% CI: 0.557-0.585, P < 1.145E-299). In stage 2, we found that both increase in educational attainment (odds ratio (OR) = 0.72, 95% CI: 0.66-0.78, P = 1.39E-14) and cognitive performance (OR = 0.69, 95% CI: 0.64-0.75, P = 1.78E-20) could reduce the risk of AD. In stage 3, we found that educational attainment may protect against AD dependently of cognitive performance (OR = 1.07, 95% CI: 0.90-1.28, P = 4.48E-01), and cognitive performance may protect against AD independently of educational attainment (OR = 0.69, 95% CI: 0.53-0.89, P = 5.00E-03). In stage 4, we found significant causal effects of cognitive performance on intelligence (beta = 0.907, 95% CI: 0.877-0.938, P < 1.145E-299), and vice versa (beta = 0.957, 95% CI: 0.937-0.978, P < 1.145E-299). In stage 5, we identified that cognitive performance may protect against AD independently of intelligence (OR = 0.74, 95% CI: 0.61-0.90, P = 2.00E-03), and intelligence may protect against AD dependently of cognitive performance (OR = 1.17, 95% CI: 0.40-3.43, P = 4.48E-01). Collectively, our univariable and multivariable MR analyses highlight the protective role of cognitive performance in AD independently of educational attainment and intelligence. In addition to the intelligence, we extend the mechanisms underlying the associations of educational attainment with AD.

Mendelian randomization highlights significant difference and genetic heterogeneity in clinically diagnosed Alzheimer's disease GWAS and self-report proxy phenotype GWAX.

BACKGROUND: Until now, Mendelian randomization (MR) studies have investigated the causal association of risk factors with Alzheimer's disease (AD) using large-scale AD genome-wide association studies (GWAS), GWAS by proxy (GWAX), and meta-analyses of GWAS and GWAX (GWAS+GWAX) datasets. However, it currently remains unclear about the consistency of MR estimates across these GWAS, GWAX, and GWAS+GWAX datasets. METHODS: Here, we first selected 162 independent educational attainment genetic variants as the potential instrumental variables (N = 405,072). We then selected one AD GWAS dataset (N = 63,926), two AD GWAX datasets (N = 314,278 and 408,942), and three GWAS+GWAX datasets (N = 388,324, 455,258, and 472,868). Finally, we conducted a MR analysis to evaluate the impact of educational attainment on AD risk across these datasets. Meanwhile, we tested the genetic heterogeneity of educational attainment genetic variants across these datasets. RESULTS: In AD GWAS dataset, MR analysis showed that each SD increase in years of schooling (about 3.6 years) was significantly associated with 29% reduced AD risk (OR=0.71, 95% CI: 0.60-0.84, and P=1.02E-04). In AD GWAX dataset, MR analysis highlighted that each SD increase in years of schooling significantly increased 84% AD risk (OR=1.84, 95% CI: 1.59-2.13, and P=4.66E-16). Meanwhile, MR analysis suggested the ambiguous findings in AD GWAS+GWAX datasets. Heterogeneity test indicated evidence of genetic heterogeneity in AD GWAS and GWAX datasets. CONCLUSIONS: We highlighted significant difference and genetic heterogeneity in clinically diagnosed AD GWAS and self-report proxy phenotype GWAX. Our MR findings are consistent with recent findings in AD genetic variants. Hence, the GWAX and GWAS+GWAX findings and MR findings from GWAX and GWAS+GWAX should be carefully interpreted and warrant further investigation using the AD GWAS dataset.

Mendelian randomization to evaluate the effect of plasma vitamin C levels on the risk of Alzheimer's disease.

OBJECTIVE: Until now, observational studies have explored the impact of vitamin C intake on Alzheimer's disease (AD) risk, however, reported ambiguous findings. To develop effective therapies or prevention, the causal link between vitamin C levels and AD should be established. METHODS: Here, we selected 11 plasma vitamin C genetic variants from a large-scale plasma vitamin C GWAS dataset (N = 52,018) as the potential instrumental variables. We extracted their corresponding summary statistics from large-scale IGAP clinically diagnosed AD GWAS dataset (N = 63,926) and UK Biobank AD proxy phenotype GWAS dataset (N = 314,278), as well as two UK Biobank subgroups including the maternal AD group (27,696 cases of maternal AD and 260,980 controls) and paternal AD group (14,338 cases of paternal AD and 245,941 controls). We then performed a Mendelian randomization (MR) study to evaluate the causal association between plasma vitamin C levels and the risk of AD and AD proxy phenotype. Meanwhile, we further verified these findings using a large-scale cognitive performance GWAS dataset (N = 257,841). RESULTS: In IGAP, we found no significant causal association between plasma vitamin C levels and the risk of AD. In UK Biobank, we found that per 1 SD increase in plasma vitamin C levels (about 20.2 µmol/l) was significantly associated with the reduced risk of AD proxy phenotype (OR = 0.93, 95% CI 0.88-0.98, P = 7.00E-03). A subgroup MR analysis in UK Biobank indicated that per 1 SD increase in plasma vitamin C levels could significantly reduce the risk of AD proxy phenotype in the maternal AD group (OR = 0.89, 95% CI 0.84-0.94, P = 7.29E-05), but not in the paternal AD group (OR = 1.02, 95% CI 0.92-1.12, P = 7.59E-01). The leave-one-out permutation further showed that the SLC23A1 rs33972313 variant largely changed the precision of the overall MR estimates in all these four GWAS datasets. Meanwhile, we did not observe any significant causal effect of plasma vitamin C levels on the cognitive performance. CONCLUSION: We demonstrated that there may be no causal association between plasma vitamin C levels and the risk of AD in people of European descent. The insistent findings in clinically diagnosed AD and AD proxy phenotype may be caused by the phenotypic heterogeneity.

Effect of plasma vitamin C levels on Parkinson's disease and age at onset: a Mendelian randomization study.

BACKGROUND: Until now, epidemiological evidence regarding the association between vitamin C intake (both diet and supplements) and Parkinson's disease (PD) remains inconsistent. Hence, it is necessary to establish the causal link between vitamin C levels and PD, and further develop effective therapies or prevention. METHODS: We selected 11 newly identified plasma vitamin C genetic variants from a large-scale plasma vitamin C GWAS dataset (n = 52,018) as the effective instrumental variables, and extracted their corresponding GWAS summary statistics from PD (33,674 PD cases and 449,056 controls) and PD age at onset (AAO) (n = 28,568). We then performed a Mendelian randomization (MR) study to evaluate the causal association of plasma vitamin C levels with PD and PD AAO using inverse-variance weighted (IVW), the weighted median, MR-Egger, and MR-PRESSO test. RESULTS: We did not observe any significant association between genetically increased vitamin C levels and PD. Interestingly, we found a reduced trend of PD AAO (1.134 years) with 1 SD genetically increased vitamin C levels using IVW (beta = - 1.134, 95% CI: [- 2.515, 0.248], P = 0.108). Importantly, this trend was further successfully verified using both weighted median and MR-Egger. Each 1 SD genetically increased vitamin C levels could reduce PD AAO 1.75 and 2.592 years using weighted median (beta = - 1.750, 95% CI: [- 3.396, - 0.105], P = 0.037) and MR-Egger (beta = - 2.592, 95% CI: [- 4.623, - 0.560], P = 0.012). CONCLUSIONS: We demonstrated the causal association between genetically increased plasma vitamin C levels and reduced PD AAO in people of European descent. Randomized controlled trials are required to clarify whether diet intake or supplement, or both could reduce the AAO of PD.

Impact of serum calcium levels on total body bone mineral density: A mendelian randomization study in five age strata.

BACKGROUND & AIMS: Mendelian randomization (MR) studies have reported the causal association between serum calcium levels and bone mineral density (BMD). The results showed that genetically increased serum calcium levels in individuals with normal calcium levels did not increase BMD and could even reduce BMD. However, whether there are differences in the association between serum calcium and BMD in different age strata remains unclear. METHODS: We selected eight serum calcium genetic variants with genome-wide significance (P < 5.00E-08) as the potential instrumental variables. We conducted an MR analysis to evaluate the impact of serum calcium levels on total body BMD in five age strata, 0-15, 15-30, 30-45, 45-60, and ≥60 years, using large-scale serum calcium (61,079 individuals) and total body BMD genome-wide association study (66,628 individuals) datasets. For pleiotropy analysis, we used a manual method and four common statistical methods, namely the MR-Egger intercept, MR-PRESSO, heterogeneity, and Steiger filtering tests. For MR analysis, we selected four MR methods, namely inverse-variance weighted, weighted median, MR-Egger, and MR-PRESSO. In addition to the univariable MR analysis, we conducted a multivariate MR analysis taking into account the effect of serum parathyroid hormone levels. RESULTS: Univariable MR analysis using the inverse-variance weighted method indicated that per 0.5-mg/dL increase (about 1 standard deviation) in serum calcium levels was statistically significantly associated with reduced total body BMD only in the ≥60 years stratum (effect estimate (beta) = -0.545, 95% confidence interval (CI): -0.892 to -0.198, P = 0.002). The weighted median regression (beta = -0.446, 95% CI: -0.821 to -0.094, P = 1.40E-02) and MR-PRESSO (beta = -0.545, 95% CI: -0.892 to -0.198, P = 0.022) MR methods further supported this suggestive association. The multivariable MR analysis also found a significant association between increased serum calcium levels and reduced total body BMD in the ≥60 years stratum (beta = -0.547, 95% CI: -0.934 to -0.16, P = 0.006). CONCLUSIONS: Our results provide genetic evidence that increased serum calcium levels did not improve BMD in the general population and that the elevated serum calcium levels in generally healthy populations, especially in adults older than 60 years, may even reduce the BMD. Our results are comparable with those of recent MR findings.

PLCG2 rs72824905 Variant Reduces the Risk of Alzheimer's Disease and Multiple Sclerosis.

We aimed to evaluate the association of PLCG2 rs72824905 variant with Alzheimer's disease (AD) and multiple sclerosis (MS) using large-scale genetic association study datasets. We selected 50,024 AD cases and 467,330 controls, and 32,367 MS cases and 36,012 controls. We found moderate heterogeneity of rs72824905 in different studies. We found significant association between rs72824905 G allele and reduced AD risk (OR = 0.66, 95% CI 0.59-0.74, p = 5.91E-14). Importantly, rs72824905 G allele could also significantly reduce the risk of MS with OR = 0.94, p = 3.63E-05. Hence, the effects of rs72824905 on AD and MS are consistent.

rs1990622 variant associates with Alzheimer's disease and regulates TMEM106B expression in human brain tissues.

BACKGROUND: It has been well established that the TMEM106B gene rs1990622 variant was a frontotemporal dementia (FTD) risk factor. Until recently, growing evidence highlights the role of TMEM106B in Alzheimer's disease (AD). However, it remains largely unclear about the role of rs1990622 variant in AD. METHODS: Here, we conducted comprehensive analyses including genetic association study, gene expression analysis, eQTLs analysis, and colocalization analysis. In stage 1, we conducted a genetic association analysis of rs1990622 using large-scale genome-wide association study (GWAS) datasets from International Genomics of Alzheimer's Project (21,982 AD and 41,944 cognitively normal controls) and UK Biobank (314,278 participants). In stage 2, we performed a gene expression analysis of TMEM106B in 49 different human tissues using the gene expression data in GTEx. In stage 3, we performed an expression quantitative trait loci (eQTLs) analysis using multiple datasets from UKBEC, GTEx, and Mayo RNAseq Study. In stage 4, we performed a colocalization analysis to provide evidence of the AD GWAS and eQTLs pair influencing both AD and the TMEM106B expression at a particular region. RESULTS: We found (1) rs1990622 variant T allele contributed to AD risk. A sex-specific analysis in UK Biobank further indicated that rs1990622 T allele only contributed to increased AD risk in females, but not in males; (2) TMEM106B showed different expression in different human brain tissues especially high expression in cerebellum; (3) rs1990622 variant could regulate the expression of TMEM106B in human brain tissues, which vary considerably in different disease statuses, the mean ages at death, the percents of females, and the different descents of the selected donors; (4) colocalization analysis provided suggestive evidence that the same variant contributed to AD risk and TMEM106B expression in cerebellum. CONCLUSION: Our comprehensive analyses highlighted the role of FTD rs1990622 variant in AD risk. This cross-disease approach may delineate disease-specific and common features, which will be important for both diagnostic and therapeutic development purposes. Meanwhile, these findings highlight the importance to better understand TMEM106B function and dysfunction in the context of normal aging and neurodegenerative diseases.

Impact of Serum Calcium Levels on Alzheimer's Disease: A Mendelian Randomization Study.

BACKGROUND: Altered calcium homeostasis is hypothesized to underlie Alzheimer's disease (AD). However, it remains unclear whether serum calcium levels are genetically associated with AD risk. OBJECTIVE: To develop effective therapies, we should establish the causal link between serum calcium levels and AD. METHODS: Here, we performed a Mendelian randomization study to investigate the causal association of increased serum calcium levels with AD risk using the genetic variants from a large-scale serum calcium genome-wide association study (GWAS) dataset (61,079 individuals of European descent) and a large-scale AD GWAS dataset (54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Here, we selected the inverse-variance weighted (IVW) as the main analysis method. Meanwhile, we selected other three sensitivity analysis methods to examine the robustness of the IVW estimate. RESULTS: IVW analysis showed that the increased serum calcium level (per 1 standard deviation (SD) increase 0.5 mg/dL) was significantly associated with a reduced AD risk (OR = 0.57, 95% CI 0.35-0.95, p = 0.031). Meanwhile, all the estimates from other sensitivity analysis methods were consistent with the IVW estimate in terms of direction and magnitude. CONCLUSION: In summary, we provided evidence that increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be conducted to clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.

Impact of Vitamin D Binding Protein Levels on Alzheimer's Disease: A Mendelian Randomization Study.

Until now, observational studies, randomized controlled trials (RCTs), and Mendelian randomization (MR) studies have explored the impact of vitamin D on Alzheimer's disease (AD), and reported inconsistent findings. In MR studies, the sensitivity analysis by removing GC rs2282679 variant highlighted no association of 25OHD levels with AD risk, which indicates that vitamin D-binding protein (DBP) encoded by GC may have distinct effects on AD risk. Here, we aim to clarify this assumption. We selected the GC rs2282679 variant associated with DBP levels (p = 3.30E-76) as the instrumental variable, and extracted the summary statistics of rs2282679 variant in multiple AD GWAS datasets from IGAP, Complex Trait Genetics (CTG) lab, and UK Biobank. We then performed a MR study to investigate the causal association between DBP levels and AD. In IGAP, MR analysis showed that the genetically DBP levels (per 1 standard deviation (SD) increase 50 mg/L) were significantly associated with reduced AD risk (OR = 0.63, 95% CI: 0.45-0.89, p = 0.009). Importantly, the estimates from two sensitivity analyses were consistent with the main estimate in terms of direction and magnitude. Meanwhile, we found no causal association between DBP levels and other four AD phenotypes in CTG lab and UK Biobank. In summary, we highlight the role of DBP levels in AD risk, and provide strong support evidence that DBP may be the therapeutic agent for the treatment of AD. Meanwhile, our findings clarify the assumption that DBP may drive the observed relationship between 25OHD levels and AD.

Circulating Vitamin D Levels and Alzheimer's Disease: A Mendelian Randomization Study in the IGAP and UK Biobank.

Observational studies strongly supported the association of low levels of circulating 25-hydroxyvitamin D (25OHD) and cognitive impairment or dementia in aging populations. However, randomized controlled trials have not shown clear evidence that vitamin D supplementation could improve cognitive outcomes. In fact, some studies reported the association between vitamin D and cognitive impairment based on individuals aged 60 years and over. However, it is still unclear that whether vitamin D levels are causally associated with Alzheimer's disease (AD) risk in individuals aged 60 years and over. Here, we performed a Mendelian randomization (MR) study to investigate the causal association between vitamin D levels and AD using a large-scale vitamin D genome-wide association study (GWAS) dataset and two large-scale AD GWAS datasets from the IGAP and UK Biobank with individuals aged 60 years and over. Our results showed that genetically increased 25OHD levels were significantly associated with reduced AD risk in individuals aged 60 years and over. Hence, our findings in combination with previous literature indicate that maintaining adequate vitamin D status in older people especially aged 60 years and over, may contribute to slow down cognitive decline and forestall AD. Long-term randomized controlled trials are required to test whether vitamin D supplementation may prevent AD in older people especially those aged 60 years and may be recommended as preventive agents.

Genetic variants regulate NR1H3 expression and contribute to multiple sclerosis risk.

A recent study analyzed 2053 multiple sclerosis (MS) cases and 799 healthy controls to investigate whether five genetic variants (rs11039149, rs12221497, rs2279238, rs7120118 and rs7114704) in NR1H3 are associated with MS risk. However this study reported negative results. It is very important that the appropriate samples and approach should be used in replication studies, which may provide the correct interpretation of the results. Here, we evaluated the above findings using large-scale MS genome-wide association studies with a total of 27,148 samples including 9772 MS cases and 17,376 controls, and multiple expression quantitative trait loci datasets. The results suggest that rs7120118 and rs2279238 variants are significantly associated with MS risk, and could significantly regulate NR1H3 expression in kinds of human tissues and cells. In summary, these findings provide important supplementary information about the association between NR1H3 variants and MS risk.

Alzheimer's Disease rs11767557 Variant Regulates EPHA1 Gene Expression Specifically in Human Whole Blood.

Large-scale genome-wide association studies have reported EPHA1 rs11767557 variant to be associated with Alzheimer's disease (AD) risk in the European population. However, it is still unclear how this variant functionally contributes to the underlying disease pathogenesis. The rs11767557 variant is located approximately 3 kb upstream of EPHA1 gene. We think that rs11767557 may modify the expression of nearby genes such as EPHA1 and further cause AD risk. Until now, the potential association between rs11767557 and the expression of nearby genes has not been reported in previous studies. Here, we evaluate the potential expression association between rs11767557 and EPHA1 using multiple large-scale eQTLs datasets in human brain tissues and the whole blood. The results show that rs11767557 variant could significantly regulate EPHA1 gene expression specifically in human whole blood. These findings may further provide important supplementary information about the regulating mechanisms of rs11767557 variant in AD risk.

Genetic Variants Associated With Neurodegenerative Diseases Regulate Gene Expression in Immune Cell CD14+ Monocytes.

Until now, large-scale genome-wide association studies have identified 94 genes associated with Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Expression quantitative trait locus (eQTL) analysis showed that six genetic variants around six of these 94 genes could drive both disease susceptibility and altered expression of six nearby genes including CD33 (rs3865444), PILRB (rs1476679), NUP160 (rs10838725), LRRK2 (rs76904798), RGS1 (rs1323292), and METTL21B (rs701006). However, two of these six genetic variants rs1476679 and rs76904798 variants could regulate the expression of PILRB and LRRK2 only in the human monocyte-derived microglia-like (MDMi) cells, but not in human peripheral blood monocytes. Here, we aim to verify these findings using another two eQTL datasets in human peripheral blood immune cell CD14+ monocytes. The results that showed that rs1476679 and rs76904798 variants or their proxy variants could significantly regulate the expression of PILRB and LRRK2 in immune cell CD14+ monocytes and human peripheral blood. We believe that these findings provide important supplementary information about the regulatory mechanisms by which both variants influence PILRB and LRRK2 gene expression and neurodegenerative disease risk.