Set-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Cohorts
2.2. Data Processing
2.3. Functional Annotation of Variants
2.4. Set-Based eQTL Analysis
2.4.1. Gene-Level cis-eQTL Analysis
2.4.2. Pathway-Level cis-eQTL Analysis
2.4.3. Comparison of Rare and Common eQTLs
3. Results
3.1. Gene-Level eQTL Associations
3.2. Variant-Level eQTL Associations
3.3. Pathways Enriched in the Brain and Blood
3.4. Gene Targets of eQTLs in the Brain and Blood
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
Aβ | amyloid-β |
AD | Alzheimer disease |
ADNI | Alzheimer’s Disease Neuroimaging Initiative |
eQTL | Expression quantitative trait locus |
CADD | Combined annotation-dependent depletion |
GWAVA | Genome-wide annotation of variants |
MAF | Minor allele frequency |
MCI | Mild cognitive impairment |
ME | module eigengene |
PANTHER | Protein Analysis Through Evolutionary Relationships |
ROSMAP | Religious Orders Study/Memory and Aging Project |
SNP | Single nucleotide polymorphism |
SVA | Surrogate variable analysis |
WCGNA | Weighted gene co-expression network analysis |
WGS | Whole-genome sequence |
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Dataset | Race | N | AD Cases | MCI Cases | Controls | Female | Age * |
---|---|---|---|---|---|---|---|
ROSMAP (Brain) | NHW 98% AA 2% Other <0.01% | 475 | 281 | 0 | 194 | 63% | 85.9 (4.8) |
ADNI (Blood) | NHW 93% AA 4% Other 3% | 713 | 207 | 284 | 222 | 44% | 76.3 (8.1) |
Chr | Begin Position | End Position | Gene | Brain | Blood | ||||
---|---|---|---|---|---|---|---|---|---|
CVar + | Unique Var ^ | p-Value | CVar + | Unique Var ^ | p-Value | ||||
6 | 41,942,338 | 43,929,364 | GNMT | 671 | 437 | 1.85 × 10−6 | 1006 | 640 | 2.87 × 10−7 |
11 | 17,434,230 | 19,468,040 | LDHC | 429 | 273 | 2.07 × 10−7 | 762 | 473 | 2.25 × 10−10 |
15 | 64,039,999 | 66,063,761 | RBPMS2 | 404 | 249 | 9.90 × 10−8 | 648 | 417 | 1.69 × 10−36 |
16 | 67,034,867 | 69,106,452 | DUS2 | 714 | 482 | 1.98 × 10−6 | 1085 | 723 | 6.41 × 10−08 |
16 | 71,090,452 | 73,094,829 | HP | 741 | 461 | 2.28 × 10−9 | 1206 | 750 | 2.43 × 10−11 |
Pathway | # Genes in Pathway | Gene Module | # Module Genes in Pathway | Module Genes | Uncorrected p-Value | FDR | ||
---|---|---|---|---|---|---|---|---|
Expected # of Genes * | Fold Enrichment † | +/− | ||||||
BRAIN | ||||||||
Apoptosis signaling | 77 | 7 | 12 | 1.64 | 7.3 | + | 3.09 × 10−7 | 5.01 × 10−5 |
Toll receptor signaling | 32 | 8 | 6 | 0.46 | 12.97 | + | 1.45 × 10−5 | 2.36 × 10−3 |
Wnt signaling | 235 | 4 | 21 | 7.35 | 2.86 | + | 3.49 × 10−5 | 5.65 × 10−3 |
Cadherin signaling | 127 | 4 | 14 | 3.97 | 3.53 | + | 9.59 × 10−5 | 7.77 × 10−3 |
CCKR signaling map | 111 | 7 | 10 | 2.37 | 4.22 | + | 2.22 × 10−4 | 1.20 × 10−2 |
Gonadotropin-releasing hormone receptor | 152 | 4 | 14 | 4.75 | 2.95 | + | 5.28 × 10−4 | 2.14 × 10−2 |
p53 | 62 | 7 | 7 | 1.32 | 5.29 | + | 5.76 × 10−4 | 2.33 × 10−2 |
Inflammation mediated by chemokine and cytokine signaling | 173 | 16 | 5 | 0.51 | 9.89 | + | 1.54 × 10−4 | 2.50 × 10−2 |
Angiogenesis | 126 | 4 | 12 | 3.94 | 3.05 | + | 9.95 × 10−4 | 3.22 × 10−2 |
BLOOD | ||||||||
Blood coagulation | 43 | 24 | 8 | 0.27 | 29.9 | + | 8.22 × 10−10 | 1.34 × 10−7 |
Parkinson’s disease | 85 | 15 | 7 | 0.79 | 8.82 | + | 2.28 × 10−5 | 3.72 × 10−3 |
Inflammation mediated by chemokine and cytokine signaling | 237 | 14 | 11 | 2.27 | 4.84 | + | 2.50 × 10−5 | 4.08 × 10−3 |
T-cell activation | 73 | 32 | 4 | 0.18 | 22.02 | + | 3.87 × 10−5 | 6.30 × 10−3 |
B-cell activation | 66 | 12 | 6 | 0.66 | 9.08 | + | 7.89 × 10−5 | 1.29 × 10−2 |
PDGF signaling | 127 | 12 | 7 | 1.27 | 5.5 | + | 3.79 × 10−4 | 2.06 × 10−2 |
Apoptosis signaling | 112 | 5 | 12 | 3.15 | 3.81 | + | 1.51 × 10−4 | 2.47 × 10−2 |
JAK/STAT signaling | 17 | 7 | 4 | 0.28 | 14.33 | + | 3.21 × 10−4 | 2.62 × 10−2 |
Ras | 64 | 5 | 8 | 1.8 | 4.44 | + | 7.61 × 10−4 | 3.10 × 10−2 |
CCKR signaling map | 164 | 5 | 14 | 4.61 | 3.04 | + | 3.94 × 10−4 | 3.21 × 10−2 |
Angiotensin II-stimulated signaling through G proteins and β-arrestin | 33 | 5 | 6 | 0.93 | 6.47 | + | 6.14 × 10−4 | 3.34 × 10−2 |
Histamine H2 receptor-mediated signaling | 24 | 5 | 5 | 0.67 | 7.41 | + | 1.03 × 10−3 | 3.37 × 10−2 |
Inflammation mediated by chemokine and cytokine signaling | 237 | 24 | 7 | 1.47 | 4.75 | + | 7.94 × 10−4 | 4.32 × 10−2 |
Heme biosynthesis | 11 | 6 | 4 | 0.25 | 15.93 | + | 2.74 × 10−4 | 4.47 × 10−2 |
Integrin signalling | 180 | 7 | 11 | 2.96 | 3.72 | + | 2.84 × 10−4 | 4.62 × 10−2 |
Inflammation mediated by chemokine and cytokine signaling | 237 | 20 | 8 | 1.78 | 4.48 | + | 5.07 × 10−4 | 8.26 × 10−2 |
CHR | Begin Position | End Position | Gene | CVAR + | Unique VAR ^ | p-Value | Gene Module | Pathway |
---|---|---|---|---|---|---|---|---|
17 | 31,600,172 | 33,592,552 | CCL7 * | 340 | 206 | 1.84 × 10−5 | 16 | Inflammation mediated by chemokine and cytokine signaling |
17 | 31,648,819 | 33,621,655 | CCL8 * | 319 | 195 | 4.50 × 10−4 | 16 | Inflammation mediated by chemokine and cytokine signaling |
17 | 72,322,351 | 74,401,630 | GRB2 | 1108 | 717 | 6.04 × 10−7 | 14 | Inflammation mediated by chemokine and cytokine signaling |
2 | 217,992,496 | 220,001,949 | CXCR2 | 943 | 564 | 1.53 × 10−6 | 14 | Inflammation mediated by chemokine and cytokine signaling |
5 | 174,085,268 | 176,108,976 | HRH2 | 335 | 196 | 9.07 × 10−6 | 5 | Histamine H2 receptor mediated signaling |
1 | 25,859,096 | 27,901,441 | RPS6KA1 | 1208 | 790 | 1.01 × 10−5 | 5 | Ras Pathway, CCKR signaling map |
11 | 76,033,278 | 78,180,311 | PAK1 | 565 | 355 | 1.83 × 10−5 | 5 | Ras Pathway, CCKR Signaling map |
21 | 33,696,834 | 35,718,581 | IFNAR1 | 525 | 332 | 1.98 × 10−5 | 14 | Inflammation mediated by chemokine and cytokine signaling |
3 | 11,628,812 | 13,702,170 | RAF1 | 431 | 255 | 2.11 × 10−5 | 14 | Inflammation mediated by chemokine and cytokine signaling |
1 | 83,964,144 | 85,961,982 | GNG5 | 589 | 336 | 3.43 × 10−5 | 5 | Histamine H2 receptor mediated signaling |
9 | 115,150,150 | 117,160,754 | ALAD | 620 | 425 | 4.97 × 10−5 | 6 | Heme biosynthesis |
1 | 44,478,672 | 46,476,606 | UROD | 1061 | 649 | 5.92 × 10−5 | 6 | Heme biosynthesis |
19 | 13,202,507 | 15,228,794 | PRKACA | 767 | 501 | 7.60 × 10−5 | 5 | Histamine H2 receptor mediated signaling, CCKR signaling map |
9 | 127,005,465 | 128998618 | HSPA5 | 1235 | 692 | 7.91 × 10−5 | 15 | Parkinson disease |
8 | 21,946,761 | 23968794 | TNFRSF10C | 817 | 520 | 8.77 × 10−5 | 5 | Apoptosis signaling |
19 | 51,273,985 | 53272173 | FPR2 | 440 | 280 | 1.23 × 10−4 | 14 | Inflammation mediated by chemokine and cytokine signaling |
13 | 30,317,837 | 32,332,540 | ALOX5AP | 297 | 197 | 1.26 × 10−4 | 14 | Inflammation mediated by chemokine and cytokine signaling |
2 | 200,984,212 | 203,030,077 | CFLAR | 637 | 404 | 2.42 × 10−4 | 5 | Apoptosis signaling |
17 | 39,458,200 | 41,463,831 | STAT5A | 1093 | 708 | 3.08 × 10−4 | 12 | PDGF signaling |
14 | 50,190,597 | 52,294,891 | NIN | 516 | 323 | 3.65 × 10−4 | 12 | PDGF signaling |
12 | 49,108,257 | 51,158,233 | TMBIM6 | 1082 | 716 | 4.48 × 10−4 | 5 | Apoptosis signaling |
eQTLs in Blood | eQTLs in Brain | ||
---|---|---|---|
eGene | Reference | eGene | Reference |
ABCA7 * | [36] | ACOT1 | [37] |
ADAMTSL4 | [38] | HLA-A | [39] |
ARRB2 | [40] | HLA-DOB * | [26] |
ATG7 | [41] | HLA-DRB1 * | [35,41] |
CD36 | [42] | HLA-DRB5 * | [36] |
CREB5 | [43] | HP | [44] |
CTNNAL1 | [45] | POMC | [46] |
ECHDC3 * | [35] | RNF39 | [47,48] |
HP | [44] | ZNF253 | [49] |
KF1B | [50,51] | ||
LRRC2 | [52] | ||
MS4A6A * | [36] | ||
PADI2 | [53] | ||
PDLIM5 | [54] | ||
S100A12 | [55] | ||
SPPL3 | [56] | ||
TMEM51 | [57] | ||
TREML4 | [58] | ||
UBE4B | [59] |
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Patel, D.; Zhang, X.; Farrell, J.J.; Lunetta, K.L.; Farrer, L.A. Set-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants. Genes 2021, 12, 419. https://doi.org/10.3390/genes12030419
Patel D, Zhang X, Farrell JJ, Lunetta KL, Farrer LA. Set-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants. Genes. 2021; 12(3):419. https://doi.org/10.3390/genes12030419
Chicago/Turabian StylePatel, Devanshi, Xiaoling Zhang, John J. Farrell, Kathryn L. Lunetta, and Lindsay A. Farrer. 2021. "Set-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants" Genes 12, no. 3: 419. https://doi.org/10.3390/genes12030419
APA StylePatel, D., Zhang, X., Farrell, J. J., Lunetta, K. L., & Farrer, L. A. (2021). Set-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants. Genes, 12(3), 419. https://doi.org/10.3390/genes12030419