Supplementary Method S1. Information theory similarity between two genes based on GO Biological Processes (Gene-ITS). As extensively detailed in Pesquitea et al's review [34], the information theory definition of semantic similarity we selected (max similarity) between two genes (Gene-ITS) is described in Equation 2 using Equations 1a-b:
Gene− ITS(g1,g2 ) =maxt j∈g2
(ITSS(ti, t j ))ti∈g1
∑ + maxti∈g1
(ITSS(ti, t j ))t j∈g2
∑
| g1 |+ | g2 |Equation 2
where gene Δ, gΔ , is annotated to a set of GO terms {ta, tb, tc, …}, and | gΔ| is the count of GO terms annotated to gΔ. The Gene-ITS score ranges from 0 to 1, where 0 means no shared or subsumed GO annotations between the two genes, and 1 corresponds to identical lists of GO annotations between the two genes.
Problem:
Alzheimer’s Disease genetic “inheritance”
“Complex ?”
Scal
es o
f Bio
logi
cal M
echa
nism
s
Enriched Biological Processes (Fig.1-2)
Protein Interaction Models (Fig. 3)
“Mendelian”
>10-7 m
10-8 m
Alzheimer’s Disease 10-1 m
KEGG pathway of AD
KEGG
22 GO 37 GO 45 similar GO term pairs
A B
(Fig.3)
(Fig.2)
Mendelian Complex
1
Supplementary Figure S2. Overlap between GO biological processes enriched in single (OMIM) and complex (GWAS) inheritance Alzheimer’s genes. Empirical distributions were conducted by bootstrap (Methods) to derive the pvalue of the observed exact overlap of GO terms enriched between the OMIM genes and those of the GWAS at an unadjusted p<0.05 cutoff of enrichments (Panel A). Using information theoretic semantic similarity (ITSS, Methods), a similar empirical calculation was conducted to identify similar GO terms enriched between the studies at the same cutoff of enrichments (Panel B). Each panel presents the empirical distributions (arrows point to the observed results).
607
192
91 32 31 16 8 3 2 2 3 4 1 1 1 2 3 1 0
0
100
200
300
400
500
600
700
0 2 4 6 8 10 13 16 21 More
Num
ber o
f per
mut
atio
ns
GO term matches
Observed Pvalue=0.007 (16 matches)
A
249
386
211
81 34 16 8 8 5 1 1 0 0 0
0 50
100 150 200 250 300 350 400 450
0
0.03
0.06
0.09
0.12
0.15
0.18
0.21
0.24
0.27
0.3
0.33
0.36
Mor
e
Num
ber o
f per
mut
atio
ns
ITSS score
Observed Pvalue<0.001 (ITSS 0.32)
B
Function Intragenic SNPs Host Genes Locus p-Value Odds Ratio Reference/Platform
rs2075650 APOE 19q13.32 2E-16 NRPMID:
20460622/Illumina [537,029]
rs3764650 ABCA7 19:1.1 5E-21 1.23 GERAD+ ADGC
rs7364180 CCDC134 22q13.2 1E-06 NRPMID:
21123754/Illumina [322,557]
rs11136000 CLU 8p21.1 9E-10 1.16PMID:
19734903/Illumina [529,205]
rs3818361 CR1 1:207.8 4E-14 1.18 GERAD+
rs12044355 DISC1 1q42.2 9E-06 NRPMID:
19118814/Illumina [~2.5 million] (imputed)
rs2373115 GAB2 11q14.1 1E-10 4.06PMID:
17553421/Affymetrix[312,316]
rs11754661 MTHFD1L 6q25.1 2E-10 2.1PMID:
20885792/Illumina [483,399]
rs2573905 PCDH11X Xq21.31 2E-07 1.29PMID:
19136949/Illumina [313,504]
rs2075650 TOMM40 19q13.32 1E-06 NRPMID:
19197348/Illumina [322,557]
intron,untranslated-3 rs6859 PVRL2 19q13.32 1E-07 1.41
PMID: 18823527/Illumina
[483,399]untranslated-3 rs610932 MS4A6A 11:85.8 1E-16 0.91 GERAD+ ADGC
near-gene-3 rs4420638 APOC1 19q13.32 2E-44 NRPMID:
17998437/Affymetrix[469,438]
near-gene-5 rs3865444 CD33 19:51.7 2E-09 0.91 ADGCrs744373 BIN1 2:127.9 3E-14 1.17 GERAD+
rs9349407 CD2AP 6:47.5 9E-09 1.11 ADGC
rs62209 CUGBP2 10p14 2E-07 2.04PMID:
21379329/Illumina [565,336]
rs2121433 EPC2 2q23.1 1E-06 NRPMID:
21123754/Illumina [322,557]
rs11767557 EPHA1 7:143.1 6E-10 0.9 ADGC
rs11610206 FAM113B 12q13.11 3E-07 NRPMID:
19118814/Illumina [~2.5 million] (imputed)
rs439401 LOC100129500 19q13.32 1E-06 NRPMID:
21123754/Illumina [322,557]
rs670139 MS4A4E 11:60.0 1E-10 1.08 GERAD+ ADGC
Supplementary Table S1. Alzheimer's Disease Intragenic SNPs reported in GWAS.
intron
unknown
rs3851179 PICALM 11q14.2 1E-09 1.16PMID:
19734902/Illumina [529,205]
rs9390537 SASH1 6q24.3 8E-06 NRPMID:
19749422/Illumina [~550,000]
rs2061333 ZNF224 19q13.31 2E-06 NRPMID:
19118814/Illumina [~2.5 million] (imputed)
unknown
Gene Region MIM ID Phenotype Mutation SNP Region Function
A2M +103950 12p13.3-p12.3
.0001ALPHA-2-
MACROGLOBULIN POLYMORPHISM
A2M, VAL1000ILE rs669 missense
.0002ALPHA-2-
MACROGLOBULIN POLYMORPHISM
A2M, CYS972TYR rs1800433 missense
.0003ALPHA-2-
MACROGLOBULIN POLYMORPHISM
A2M, IVS1DEL DEL
.0004ALPHA-2-
MACROGLOBULIN POLYMORPHISM
A2M, ARG681HIS rs1800434 missense
.0005 ALZHEIMER DISEASE, SUSCEPTIBILITY TO A2M, EX18DEL DEL
.0006ALPHA-2-
MACROGLOBULIN POLYMORPHISM
A2M, 5-BP DEL DEL
AD5 %602096 12p11.23-q13.12
APOE +107741 19q13.2
.0001
HYPERLIPOPROTEINEMIA, TYPE III, AUTOSOMAL RECESSIVE
APOE, ARG158CYS rs7412 missense
.0002
HYPERLIPOPROTEINEMIA AND
ATHEROSCLEROSIS ASSOCIATED WITH
APOE5
APOE, GLU3LYS rs121918392 -
.0003
HYPERLIPOPROTEINEMIA, TYPE III, DUE TO
APOE2-CHRISTCHURCH
APOE, ARG136SER rs121918393 -
.0004
HYPERLIPOPROTEINEMIA, TYPE III,
ASSOCIATED WITH APOE2
APOE, ARG145CYS rs769455 missense
.0005
HYPERLIPOPROTEINEMIA, TYPE III,
ASSOCIATED WITH APOE DEFICIENCY
APOE, IVS3AS, A-G, -1
Alternative splicing
Supplementary Table S2. Alzheimer's Disease Intragenic SNPs reported in OMIM.
.0006
HYPERLIPOPROTEINEMIA, TYPE III,
ASSOCIATED WITH APOE LEIDEN
APOE, 21-BP INS, DUP
CODONS 121-127
INS
.0007
HYPERLIPOPROTEINEMIA, TYPE III,
ASSOCIATED WITH APOE7
APOE, GLU244LYS
AND GLU245LYS
Multiple
.0008
HYPERLIPOPROTEINEMIA, TYPE III, AUTOSOMAL DOMINANT
APOE, CYS112ARG
AND ARG142CYS
rs429358 missense
.0009 APOLIPOPROTEINEMIA E1
APOE, GLY127ASP
AND ARG148CYS
Multiple
.0010HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE1-HARRISBURG
APOE, LYS146GLU rs121918394 -
.0011 DYSBETALIPOPROTEINEMIA DUE TO APOE2
APOE, LYS146GLN rs121918394 -
.0012 HYPERLIPOPROTEINEMIA, TYPE IV/V
APOE, ARG228CYS rs121918395 -
.0013HYPERLIPOPROTEINEMIA, TYPE III, DUE TO APOE4-PHILADELPHIA
APOE, GLU13LYS AND
ARG145CYSMultiple
.0014
HYPERLIPOPROTEINEMIA, TYPE III,
ASSOCIATED WITH APOE DEFICIENCY
APOE, TRP210TER rs121918396 -
.0015 APOE3 ISOFORM APOE, CYS112 AND ARG158 Multiple
.0016 ALZHEIMER DISEASE 2 APOE, CYS112ARG rs429358 missense
.0017
HYPERLIPOPROTEINEMIA, TYPE III,
ASSOCIATED WITH APOE DEFICIENCY,
AUTOSOMAL RECESSIVE
APOE, 1-BP DEL, 2919G
DEL, FS60TERDEL
.0018 HYPERLIPOPROTEINEMIA, TYPE III
APOE, ARG145HIS rs121918397 -
.0019
HYPERLIPOPROTEINEMIA, TYPE III,
ASSOCIATED WITH APOE2-FUKUOKA
APOE, ARG158CYS
AND ARG224GLN
Multiple
.0020
HYPERCHOLESTEROLEMIA AND
HYPERTRIGLYCERIDEMIA, TYPE III
APOE, GLU3LYS AND
GLU13LYSMultiple
.0021
HYPERLIPOPROTEINEMIA, TYPE III,
ASSOCIATED WITH APOE2
APOE, ARG158CYS
AND VAL236GLU
Multiple
.0022
HYPERLIPOPROTEINEMIA, TYPE III,
ASSOCIATED WITH APOE4
APOE, CYS112ARG
AND ARG251GLY
Multiple
.0023 APOE4(-)-FREIBURG
APOE, LEU28PRO
AND CYS112ARG
rs769452 missense
.0024 APOE3(-)-FREIBURG APOE, THR42ALA rs28931576 unknown
.0025 APOE4 VARIANT
APOE, PRO84ARG
AND CYS112ARG
Multiple
.0026 APOE3 VARIANT
APOE, ALA99THR
AND ALA152PRO
Multiple
.0027 APOE2 VARIANT APOE, ARG134GLN rs28931578 missense
.0028 APOE4 VARIANT APOE, ARG274HIS rs121918398 -
.0029 APOE4(+) APOE, SER296ARG rs28931579 untranslated-5
.0030MYOCARDIAL INFARCTION,
SUSCEPTIBILITY TOAPOE, -219G-T rs405509 -
.0031 SEA-BLUE HISTIOCYTE DISEASE
APOE, 3-BP DEL, 499CTC DEL
.0032 LIPOPROTEIN GLOMERULOPATHY
APOE, ARG145PRO rs121918397 -
.0033 LIPOPROTEIN GLOMERULOPATHY
APOE, ARG25CYS rs121918399 -
APP +104760 21q21
.0001
CEREBRAL AMYLOID ANGIOPATHY, APP-RELATED, DUTCH
VARIANT
APP, GLU693GLN rs63750579 missense,untrans
lated-3
.0002 ALZHEIMER DISEASE, FAMILIAL, 1
APP, VAL717ILE rs63750264 missense
.0003 ALZHEIMER DISEASE, FAMILIAL, 1
APP, VAL717PHE rs63750264 -
.0004 ALZHEIMER DISEASE, FAMILIAL, 1
APP, VAL717GLY rs63749964 missense
.0005
CEREBRAL AMYLOID ANGIOPATHY, APP-RELATED, FLEMISH
VARIANT
APP, ALA692GLY rs63750671 missense
.0007 APP POLYMORPHISM APP, 2124C-T Allelic Variant(.0007)
.0008 ALZHEIMER DISEASE, FAMILIAL, 1
APP, LYS670ASN
AND MET671LEU
rs63750445 missense
.0008 ALZHEIMER DISEASE, FAMILIAL, 1
APP, LYS670ASN
AND MET671LEU
rs63751263 missense
.0009 ALZHEIMER DISEASE, FAMILIAL, 1
APP, ALA713THR rs63750066 coding-
synon,missense
.0010 ALZHEIMER DISEASE, FAMILIAL, 1
APP, GLU665ASP rs63750363 missense
.0011 ALZHEIMER DISEASE, FAMILIAL, 1
APP, ILE716VAL rs63750399 coding-
synon,missense
.0012 ALZHEIMER DISEASE, FAMILIAL, 1
APP, VAL715MET rs63750734 coding-
synon,missense
.0013 ALZHEIMER DISEASE, FAMILIAL, 1
APP, GLU693GLY rs63751039 missense
.0014
CEREBRAL AMYLOID ANGIOPATHY, APP-RELATED, ITALIAN
VARIANT
APP, GLU693LYS rs63750579 missense,untrans
lated-3
.0015 ALZHEIMER DISEASE, FAMILIAL, 1
APP, THR714ILE rs63750973 missense
.0016
CEREBRAL AMYLOID ANGIOPATHY, APP-
RELATED, IOWA VARIANT
APP, ASN694ASP
Allelic Variant(.0016)
.0017 ALZHEIMER DISEASE, FAMILIAL, 1
APP, THR714ALA rs63750643 coding-
synon,missense
.0019
CEREBRAL AMYLOID ANGIOPATHY, APP-
RELATED, PIEDMONT VARIANT
APP, LEU705VAL rs63750921 missense
.0020
ALZHEIMER DISEASE, EARLY-ONSET, WITH CEREBRAL AMYLOID
ANGIOPATHY
APP, DUP DUP
.0021 ALZHEIMER DISEASE, FAMILIAL, 1
APP, VAL717LEU
Allelic Variant(.0021)
.0022
DEMENTIA, EARLY-ONSET PROGRESSIVE,
AUTOSOMAL RECESSIVE
APP, ALA673VAL
Allelic Variant(.0022)
DCR #190685 21q22.3
HFE *613609 6p21.3
.0001 ALZHEIMER DISEASE, SUSCEPTIBILITY TO
HFE, CYS282TYR rs1800562 -
.0002 HEMOCHROMATOSIS HFE, HIS63ASP rs1799945 intron,missense
.0003 HEMOCHROMATOSIS HFE, SER65CYS rs1800730 intron,missense
.0004 HFE INTRONIC POLYMORPHISM HFE, 5569G-A Allelic
Variant(.0004)
.0005 HFE POLYMORPHISM HFE, VAL53MET rs28934889 intron,missense
.0006 HFE POLYMORPHISM HFE, VAL59MET rs111033557 intron,missense
.0007 HEMOCHROMATOSIS HFE, GLN127HIS rs28934595 intron,missense
.0008 HEMOCHROMATOSIS HFE, ARG330MET rs111033558 missense
.0009 HEMOCHROMATOSIS HFE, ILE105THR rs28934596 intron,missense
.0010 HEMOCHROMATOSIS HFE, GLY93ARG rs28934597 intron,missense
.0011 HEMOCHROMATOSIS HFE, GLN283PRO rs111033563 intron,missense
MPO *606989 17q23.1
.0001 MYELOPEROXIDASE DEFICIENCY
MPO, ARG569TRP rs119468010 missense
.0002 MYELOPEROXIDASE DEFICIENCY
MPO, TYR173CYS rs78950939 missense
.0003 MYELOPEROXIDASE DEFICIENCY
MPO, MET251THR rs56378716 missense
.0004 MYELOPEROXIDASE DEFICIENCY
MPO, 14-BP DEL DEL
.0005 MYELOPEROXIDASE DEFICIENCY
MPO, ALA332VAL rs28730837 missense
.0006 MYELOPEROXIDASE DEFICIENCY
MPO, LEU572TRP rs119469012 missense
.0007 MYELOPEROXIDASE DEFICIENCY
MPO, IVS11AS, A-C, -2, 109-BP
DELDEL
.0008 ALZHEIMER DISEASE, SUSCEPTIBILITY TO MPO, -463G-A Allelic
Variant(.0008)
.0009 MYELOPEROXIDASE DEFICIENCY
MPO, GLY501SER rs119469013 missense
.0010 MYELOPEROXIDASE DEFICIENCY
MPO, ARG499CYS rs119469014 missense
NOS3 +163729 7q36ALZHEIMER DISEASE,
LATE-ONSET, SUSCEPTIBILITY TO,
INCLUDED.0001 NOS3, GLU298ASP rs1799983 missense
CORONARY ARTERY SPASM 1,
SUSCEPTIBILITY TO
.0002CORONARY ARTERY
SPASM 1, SUSCEPTIBILITY TO
NOS3, -786T-C Allelic Variant(.0002)
PLAU *191840 10q24
.0001ALZHEIMER DISEASE,
LATE-ONSET, SUSCEPTIBILITY TO
PLAU, PRO141LEU rs2227564 intron,missense
PRNP *176640 20pter-p12
.0001 CREUTZFELDT-JAKOB DISEASE
PRNP, EXTRA OCTAPEPTIDE
CODING REPEATS
DUP
.0002 GERSTMANN-STRAUSSLER DISEASE
PRNP, PRO102LEU rs74315401 missense
.0004 GERSTMANN-STRAUSSLER DISEASE
PRNP, ALA117VAL rs74315402 missense
.0005ALZHEIMER DISEASE,
EARLY-ONSET, SUSCEPTIBILITY TO,
PRNP, MET129VAL rs1799990 missense
.0006 CREUTZFELDT-JAKOB DISEASE
PRNP, GLU200LYS rs28933385 missense
.0007 CREUTZFELDT-JAKOB DISEASE
PRNP, ASP178ASN
AND MET129VAL
rs1799990 missense
.0007 CREUTZFELDT-JAKOB DISEASE
PRNP, ASP178ASN
AND MET129VAL
rs74315403 missense
.0010 FATAL FAMILIAL INSOMNIA
PRNP, ASP178ASN AND MET129
rs74315403 missense
.0011 GERSTMANN-STRAUSSLER DISEASE
PRNP, PHE198SER rs74315405 missense
.0012 GERSTMANN-STRAUSSLER DISEASE
PRNP, GLN217ARG rs74315406 missense
.0014 CREUTZFELDT-JAKOB DISEASE
PRNP, VAL210ILE rs74315407 missense
.0015 GERSTMANN-STRAUSSLER DISEASE
PRNP, PRO105LEU rs11538758 missense
.0016 CREUTZFELDT-JAKOB DISEASE
PRNP, VAL180ILE rs74315408 missense
.0001 NOS3, GLU298ASP rs1799983 missense
.0017 CREUTZFELDT-JAKOB DISEASE
PRNP, MET232ARG rs74315409 missense
.0018
SPONGIFORM ENCEPHALOPATHY
WITH NEUROPSYCHIATRIC
FEATURES
PRNP, ASN171SER rs16990018 missense
.0019CREUTZFELDT-JAKOB
DISEASE, PROTECTION AGAINST
PRNP, GLU219LYS rs1800014 missense
.0021 GERSTMANN-STRAUSSLER DISEASE
PRNP, GLY131VAL rs74315410 missense
.0022
SPONGIFORM ENCEPHALOPATHY
WITH NEUROPSYCHIATRIC
FEATURES
PRNP, THR183ALA rs74315411 missense
.0023 CREUTZFELDT-JAKOB DISEASE
PRNP, ARG208HIS rs74315412 missense
.0024 GERSTMANN-STRAUSSLER DISEASE
PRNP, HIS187ARG rs74315413 missense
.0025
SPONGIFORM ENCEPHALOPATHY
WITH NEUROPSYCHIATRIC
FEATURES
PRNP, PRO105THR rs74315414 missense
.0026 GERSTMANN-STRAUSSLER DISEASE
PRNP, ALA133VAL rs74315415 missense
.0027 GERSTMANN-STRAUSSLER DISEASE
PRNP, PRO105SER rs74315414 missense
.0028 KURU, PROTECTION AGAINST
PRNP, GLY127VAL
Allelic Variant(.0028)
PSEN1 *104311 14q24.3
.0001 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, MET146LEU rs63750306 missense
.0002 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, HIS163ARG rs63750590 missense
.0003 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, ALA246GLU rs63750526 missense
.0004 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, LEU286VAL rs63751235 missense
.0005 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, CYS410TYR rs661 missense
.0006 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, MET139VAL rs63751037 missense
.0007 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, MET146VAL rs63750306 -
.0008 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, HIS163TYR rs63749885 missense
.0009 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, GLU280ALA rs63750231 missense
.0010 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, GLU280GLY rs63750231 -
.0011 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, PRO267SER rs63751229 missense
.0012 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, IVS8AS, G-T, -
1, EX9DELDEL
.0013 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, GLU120ASP rs63751272 missense
.0014 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, ALA426PRO rs63751223 missense
.0015 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, MET146ILE rs63750391 missense
.0016 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, LEU250SER rs63751163 missense
.0017
ALZHEIMER DISEASE, FAMILIAL, WITH
SPASTIC PARAPARESIS AND UNUSUAL PLAQUES
PSEN1, ARG278THR rs63749891 missense
.0018 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, IVS4DS, 1-BP
DEL, GDEL
.0019 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, 1548GC-TG Multiple
.0020 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, CYS92SER rs63751141 missense
.0021 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, GLY206ALA rs63750082 missense
.0022
ALZHEIMER DISEASE, FAMILIAL, 3, WITH
SPASTIC PARAPARESIS AND
APRAXIA
PSEN1, GLY266SER
Allelic Variant(.0022)
.0023 DEMENTIA, FRONTOTEMPORAL
PSEN1, LEU113PRO rs63751399 missense
.0024 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, LEU166PRO rs63750265 missense
.0025 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, LEU174MET rs63751144 missense
.0026ALZHEIMER DISEASE,
FAMILIAL, 3, WITH UNUSUAL PLAQUES
PSEN1, LEU271VAL rs63750886 missense
.0027 PICK DISEASE OF BRAIN
PSEN1, GLY183VAL rs63751068 missense
.0028 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, PRO436GLN
Allelic Variant(.0028)
.0029
ALZHEIMER DISEASE, FAMILIAL, 3, WITH
SPASTIC PARAPARESIS AND UNUSUAL PLAQUES
PSEN1, 6-BP INS, NT715 INS
.0030 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, ARG278ILE rs63749891 missense
.0031
ALZHEIMER DISEASE, FAMILIAL, 3, WITH
SPASTIC PARAPARESIS AND
APRAXIA
PSEN1, LEU85PRO rs63750599 missense
.0032
ALZHEIMER DISEASE, FAMILIAL, 3, WITH
SPASTIC PARAPARESIS AND UNUSUAL PLAQUES
PSEN1, 3-BP DEL DEL
.0033 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, ALA431GLU rs63750083 missense
.0034 CARDIOMYOPATHY, DILATED, 1U
PSEN1, ASP333GLY Allelic Variant()
.0035 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, ALA79VAL rs63749824 missense
.0036 ALZHEIMER DISEASE, FAMILIAL, 3
PSEN1, SER170PHE rs63750577 missense
.0037ALZHEIMER DISEASE,
FAMILIAL, 3, WITH UNUSUAL PLAQUES
PSEN1, GLY217ARG
Allelic Variant(.0037)
.0038 ACNE INVERSA, FAMILIAL, 3
PSEN1, 1-BP DEL, 725C DEL
PSEN2 *600759 1q31-q42
.0001 ALZHEIMER DISEASE, FAMILIAL, 4
PSEN2, ASN141ILE rs63750215 missense
.0002 ALZHEIMER DISEASE, FAMILIAL, 4
PSEN2, MET239VAL rs28936379 missense
.0003 ALZHEIMER DISEASE, FAMILIAL, 4
PSEN2, ASP439ALA rs63750110 missense
.0004 ALZHEIMER DISEASE, FAMILIAL, 4
PSEN2, THR430MET rs63750666 missense
.0005 ALZHEIMER DISEASE, FAMILIAL, 4
PSEN2, THR122PRO rs63749851 missense
.0006 ALZHEIMER DISEASE, FAMILIAL, 4
PSEN2, MET239ILE rs63749884 missense
.0007 ALZHEIMER DISEASE, FAMILIAL, 4
PSEN2, THR122ARG
Allelic Variant(.0007)
.0008 CARDIOMYOPATHY, DILATED, 1V
PSEN2, SER130LEU rs63750197 missense
.0009 ALZHEIMER DISEASE, FAMILIAL, 4
PSEN2, ALA85VAL rs63750048 missense
SNCA *163890 4q21
.0001PARKINSON DISEASE 1,
AUTOSOMAL DOMINANT
SNCA, ALA53THR rs104893877 missense
.0002PARKINSON DISEASE 1,
AUTOSOMAL DOMINANT
SNCA, ALA30PRO rs104893878 missense
.0003PARKINSON DISEASE 4,
AUTOSOMAL DOMINANT
SNCA, TRIPLICATION TRP
.0004 DEMENTIA, LEWY BODY
SNCA, GLU46LYS rs104893875 missense
.0005PARKINSON DISEASE 1,
AUTOSOMAL DOMINANT
SNCA, DUPLICATION DUP
TF +190000 6p21.3, 3q21
.0001 TRANSFERRIN VARIANT D1 TF, GLY277ASP rs121918676 -
.0002 TRANSFERRIN VARIANT CHI TF, HIS300ARG rs41295774 missense
.0003 TRANSFERRIN VARIANT B2 TF, GLY652GLU rs121918677 -
.0004 ALZHEIMER DISEASE, SUSCEPTIBILITY TO
TF, PRO570SER rs1049296 missense
.0005 TRANSFERRIN VARIANT Bv TF, LYS627GLU rs121918678 -
.0006 ATRANSFERRINEMIA TF, 10-BP DEL AND 9-BP DUP DEL DUP
.0007 ATRANSFERRINEMIA TF, ALA477PRO rs121918679 -
.0009 ATRANSFERRINEMIA TF, GLU375LYS rs121918680 -
.0010 ATRANSFERRINEMIA TF, ASP77ASN rs121918681 -
TNF *191160 6p21.3
.0001 TNF RECEPTOR BINDING, ALTERED
TNF, LEU29SER
Allelic Variant(.0001)
.0002 TNF RECEPTOR BINDING, ALTERED
TNF, ARG32TRP
Allelic Variant(.0002)
.0003 MALARIA, CEREBRAL, SUSCEPTIBILITY TO TNF, -376G-A Allelic
Variant(.0003)
.0004 SEPTIC SHOCK, SUSCEPTIBILITY TO TNF, -308G-A Allelic
Variant(.0004)VASCULAR DEMENTIA,
SUSCEPTIBILITY TOALZHEIMER DISEASE, SUSCEPTIBILITY TO,
.0006 ALZHEIMER DISEASE, PROTECTION AGAINST TNF, -863C-A rs1800630 -
.0005 TNF, -850C-T rs1799724 near-gene-3,near-gene-5
VEGFA +192240 6p12
.0001
MICROVASCULAR COMPLICATIONS OF
DIABETES, SUSCEPTIBILITY TO, 1
VEGFA, -634G-C, (rs2010963) rs2010963 untranslated-5
.0002 ATHEROSCLEROSIS, SUSCEPTIBILITY TO
VEGFA, -2578C-A, (rs699947) rs699947 near-gene-5
ALZHEIMER DISEASE, SUSCEPTIBILITY TO,
INCLUDED
Accession GO term Recall rate
Genes in GO
P-value (adjusted)
Gene count
GO:0002541activation of plasma proteins
involved in acute inflammatory response
92% 3 0.02615287
GO:0002460
adaptive immune response based on somatic
recombination of immune receptors built from
immunoglobulin superfamily domains
88% 40 0.01285412 3 PVRL2 CR1 CLU
GO:0014012 axon regeneration in the peripheral nervous system 88% 5 0.0474412
GO:0030030 cell projection organization 84% 348 0.03158108 3 CD2AP PVRL2 PICALM
GO:0006958 complement activation, classical pathway 92% 47 0.01741573 2 CLU CR1
GO:0051234 establishment of localization 72% 2806 0.03158108 6 ABCA7 TOMM40 PICALM APOC1 PVRL2 CLU
GO:0034375 high-density lipoprotein particle remodeling 96% 14 0.0059252 1 APOC1
GO:0006959 humoral immune response 88% 97 0.04883731 2 CLU CR2
GO:0016064 immunoglobulin mediated immune response 88% 217 0.03158108 3 CR1 CLU PVRL2
GO:0002449 lymphocyte mediated immunity 88% 32 0.01184661 5 PVRL2 CR1 CLU PICALM TOMM40
GO:0033036 macromolecule localization 80% 194 0.03158108 2 APOC1 CLUGO:0010324 membrane invagination 96% 0.00014023 2 ABCA7 PICALM
GO:0045541negative regulation of
cholesterol biosynthetic process
92% 3 0.03820839
GO:0010900negative regulation of
phosphatidylcholine catabolic process
96% 1 0.02411578 1 APOC1
GO:0048261negative regulation of
receptor-mediated endocytosis
92% 6 0.00196577 2 APOC1 PICALM
GO:0010873 positive regulation of 96% 7 0.00229159 1 APOC1GO:0045834 positive regulation of lipid
metabolic process 96% 62 0.03158108 1 APOC1
GO:0032805positive regulation of low-
density lipoprotein receptor catabolic process
100% 1 0.02411578
GO:0034368 protein-lipid complex 96% 22 0.01184661 1 APOC1 APOEGO:0032879 regulation of localization 84% 967 0.02411578 4 BIN1 APOC1 PICALM GAB2
Supplementary Table S3. GO terms enriched from GWAS genes
Gene symbols
GO:0042271 susceptibility to natural killer cell mediated cytotoxicity 88% 4 0.03820839 1 PVRL2
GO:0060370 susceptibility to T cell mediated cytotoxicity 92% 2 0.03158108 1 PVRL2
Accession GO term Recall Rate Genes in GO
P-value (adjusted)
Gene count
GO:0002253 activation of immune response 100% 238 2.48E-03 2 PSEN1 PSEN2
GO:0048667 cell morphogenesis involved in neuron differentiation 87% 7 4.12E-02 3 APP PRNP PSEN1
GO:0048669 collateral sprouting in the absence of injury 93% 3 7.29E-03 1 APP
GO:0006955 immune response 100% 628 1.33E-03 4 HFE APP TNF VEGFA
GO:0051179 localization 67% 236 2.88E-02 1 TNF
GO:0034374 low-density lipoprotein particle remodeling 93% 10 2.88E-02 1 MPO
GO:0050771 negative regulation of axonogenesis 93% 29 4.73E-02 1 PSEN1
GO:0001869 negative regulation of complement activation, lectin pathway 93% 2 1.11E-02 1 A2M
GO:0002921 negative regulation of humoral immune response 93% 5 1.68E-02 1 A2M
GO:0002698 negative regulation of immune effector process 93% 38 3.79E-02 1 A2M
GO:0050995 negative regulation of lipid catabolic process 93% 14 3.45E-02 1 TNF
GO:0010955 negative regulation of protein maturation by peptide bond cleavage 93% 8 2.13E-02 1 A2M
GO:0048812 neuron projection morphogenesis 87% 117 4.21E-02 1 APP
GO:0007220 Notch receptor processing 100% 16 4.73E-04 2 PSEN1 PSEN2
GO:0002821 positive regulation of adaptive immune response 93% 41 4.86E-02 1 TNF
GO:0002714 positive regulation of B cell mediated immunity 93% 12 2.95E-02 1 TNF
GO:0009891 positive regulation of biosynthetic process 80% 975 4.27E-02 4 APP SNCA TNF VEGFA
GO:0032270 positive regulation of cellular protein metabolic process 87% 396 4.20E-02 4 PSEN1 SNCA TNF VEGFA
GO:0002925 positive regulation of humoral immune response mediated by circulating immunoglobulin 93% 6 2.34E-02 1 TNF
GO:0002705 positive regulation of leukocyte mediated immunity 87% 42 4.96E-02 1 TNF
GO:0045940 positive regulation of steroid metabolic process 93% 18 3.68E-02 1 TNF
Supplementary Table S4. GO terms enriched from OMIM genes
Gene symbols
GO:0051604 protein maturation 100% 82 2.68E-03 2 PSEN1 PSEN2
GO:0051605 protein maturation by peptide bond cleavage 87% 49 5.49E-03 2 PSEN1 PSEN2
GO:0034368 protein-lipid complex remodeling 93% 22 4.12E-02 1 MPO APOE
GO:0032800 receptor biosynthetic process 93% 5 3.21E-02 1 TNF
GO:0031623 receptor internalization 93% 23 4.36E-02 1 SNCA
GO:0030449 regulation of complement activation 93% 6 1.68E-02 1 A2M
GO:0002718 regulation of cytokine production involved in immune response 93% 31 3.88E-02 1 TNF
GO:0002889 regulation of immunoglobulin mediated immune response 93% 27 4.36E-02 1 TNF
GO:0002861 regulation of inflammatory response to antigenic stimulus 93% 16 2.88E-02 1 TNF
GO:0019216 regulation of lipid metabolic process 87% 149 2.34E-02 2 SNCA TNF
GO:0032879 regulation of localization 80% 967 2.25E-02 5 NOS3 PLAU SNCA TNF VEGFA
GO:0070613 regulation of protein processing 87% 14 2.72E-02 1 A2M
GO:0050810 regulation of steroid biosynthetic process 93% 34 4.73E-02 1 TNF
GO:0043403 skeletal muscle tissue regeneration 93% 8 2.95E-02 1 PLAU
GO:0048488 synaptic vesicle endocytosis 73% 5 3.21E-02 1 SNCA
GO:0042088 T-helper 1 type immune response 93% 8 3.79E-02 1 VEGFA
GO Biomodule GO biological process "ancestor node"
GO biological process "child node" AD pathological mechanism Reference
Regulation of localizationEstablishment of
localizationMacromoleclue
localizationMembrane invagination
Receptor internalization
Synaptic vesicle endocytosis
Negative regulation of receptor-medicated
endocytosis
Cell projection organization
Collateral sprouting in the absence of injuryNegative regulation of
axonogenesisNeuron projection morphogenesis
Cell morphogenesis involved in neuron
differentiationPositive regulation of lipid
metabolic processNegative regulation of lipid catabolic process
Regulation of steroid biosynthetic process
Positive regulation of steroid metabolic process
Since the blood-brain barrier preventsany efficient exchange between brainand plasma lipoproteins, the majorityof brain cholesterol is derived from denovo biosynthesis, rather than fromplasma LDL [9,10].
[9] Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Curr Opin Lipidol. 2001;12(2):105-112. [10] Vance JE, Hayashi H, Karten B. Cholesterol homeostasis in neurons and glial cells. Semin Cell Dev Biol. 2005;16(2):193-212.
Positive regulation of cholesterol esterification NA
Excess free cholesterol in the cell isconverted into cholesteryl esters byACAT1 followed by accumulation inintracellular lipid droplets or effluxthrough the plasma membrane into theextracellular environment. Increasinglevels of cholesteryl esters enhancesamyloid-β release in cultured cells[11,12].
[11] Chang TY, Chang CC, Ohgami N, Yamauchi Y. Cholesterol sensing, trafficking, and esterification. Annu Rev Cell Dev Biol. 2006;22:129-157. [12] Puglielli L, Konopka G, Pack-Chung E, Ingano LA, Berezovska O, et al. Acyl coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide. Nature Cell Bio. 2001;3(10):905-912.
Negative regulation of cholesterol biosynthetic
processNA
Amyloid-β is known to regulate themetabolism of cholesterol andsphingolipids, both of which also affectAPP processing [13].
[13] Grimm MO, Grimm HS, Patzold AJ, Zinser EG, Halonen R, et al. Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presellin. Nature Cell Biol. 2005;7(11):1118-1123.
Supplementary Table S5. Alzheimer's disease biomodule review of literature of selected GO biological processes.
Localization and Membrane Regulation
Neuronal process
Regulation of lipid metabolic process
Brains with AD display a higheroccurrence of "adipose inclusions" or"lipoid granules," suggesting aberrantlipid metabolism [8].
[8] Foley P. Lipids in Alzheimer's disease: a century-old story. Biochi Biophys Acta. 2010;1801(8):750-753.
Localization
Lipid process
Deposition of amyloid-β peptide inbrain tissue plaques constitutes the"amyloid hypothesis" of ADpathogenesis [1].
[1] Hardy J, Selkoe J. The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics. Science. 2002;297(5580):353-6.
NA
Early endosomes are a requirementfor β-secretase activity against APPand a major cellular site for Aβproduction. Thus, mechanismsregulating material flow to and awayfrom early endosomes should regulateAPP processing. Reducing the timeAPP or β-secretase exists within earlyendosomes reduces β-cleavage andAβ production [2]. APOE acts as an Aβ-scavenging molecule that regulates Aβconcentration through internalization of APOE receptors by theendosomal/lysosomal pathway [3].
[2] Rajendran L, Simons K. Membrane Trafficking and Targeting in Alzheimer's Disease. Research and Perspectives in Alzheimer's Disease. 2009;103-113. [3] Boche D, Nicoll JAR. The Role of the Immune System in Clearance of Aβ from the Brain. Brain Pathol. 2008;18(2):267-78.
NA
Mutated or dysregulated tau proteincauses neurofibrillary tangles in brainareas associated with Alzheimer'sdisease pathology. The axon is amajor site of β-amyloid production, and overproduction of Aβ leads todystrophic axons and dendrites around amyloid plaques [4,5,6,7].
[4] Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001;293(5534):1487-1491. [5] Gunawardena S, Goldstein LS. Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron. 2001;32(3):389-401. [6] Brendza RP, Simmons K, Bales KR, et al. Use of YFP to study amyloid-beta associated neurite alterations in live brain slices. Neurobiol Aging. 2003;24(8):1071-1077. [7] Tsai J, Grutzendler J, Duff K, Gan WB. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci. 2004;7(11):1181-1183.
Negative regulation of phosphatidylcholine
processNA
The phospholipase D signalingpathway has been shown to play apart in amyloidogenesis. PLD1hydrolyses phosphatidylcholine togenerate phosphatidic acid and freecholine [14,15].
[14] Oliveira TG, Di Paolo G. Phospholipase D in brain function and Alzheimer's disease. Biochim Biophys Acta. 2010;1801(8):799-905. [15] Jenkins GM, Frohman MA. Phospholipase D: a lipid centric review. Cell Mol Life Sci. 2005;62(19-20):2305-2316.
High-density lipoprotein particle remodeling
Small amounts of cholesterol can alsobe delivered to the brain from theperiphery through high densitylipoproteins (HDLs), which can crossthe blood-brain barrier [16].
[16] Di Paolo G, Kim TW. Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat Rev Neurosci. 2011;12(5):284-96.
Low-density lipoprotein particle remodeling
Apolipoprotein E mediates the uptakeof lipoprotein particles in the brain viathe low-density lipoprotein receptorrelated protein and the very low-density family lipoprotein receptor [17].The role of the E4 allele of APOE inamyloid pathology is supported byevidence that it binds amyloid-β andmodulates the aggregation andclearance of amyloid-β [18].
[17] Bu G. Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nature Rev Neurosci. 2009;10(5):333-344. [18] Kim J, Basak JM, Holtzman DM. The role of apoliprotein E in Alzheimer's disease. Neuron. 2009;63(3):287-303.
Activation of immune response
Positive regulation of leukocyte mediated
immunity
Regulation of cytokine production involved in
immune response
Immunoreactivity for IL-1, IL-6, andTGF-β1 is associated with Aβ plaques[21,22,23]. Elevated TNF-α and TGF-β1 levels have been detected in theserum and CSF of AD patients [24,25].
[21] Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, et al. Glial-neuronal interactions in Alzheimer's disease: the potential role of a "cytokine cycle" in disease progression. Brain Pathol. 1998;8(1):65-72. [22] Hull M, Berger M, Volk B, Bauer J. Occurrence of interleukin-6 in cortical plaques of Alzheimer's disease patients may precede transformation of diffuse into neuritic plaques. Ann NY Acad Sci. 1996;777:205-212. [23] van der Wal EA, Gomez-Pinilla F, Cotman CW. Transforming growth factor-beta 1 is in plaques in Alzheimer and Down pathologies. Neuroreport. 1993;4(1):69-72. [24] Chao CC, Ala TA, Hu S, Crossley KB, Sherman RE, et al. Serum cytokine levels in patients with Alzheimer's disease. Clin Diagn Lab Immunol. 1994;1(4):433-436. [25] Chao CC, Hu S, Frey WH 2nd, Ala TA, Tourtellotte WW, Peterson PK. Transforming growth factor beta in Alzheimer's disease. Clin Diagn Lab Immunol. 1994;(1)1:109-110.
Regulation of immunoglobulin mediated
immune response
Negative regulation of humoral immune
response
Regulation of inflammatory response to antigenic stimulus
Activation of plasma proteins involved in acute
inflammatory response
Aβ is pro-inflammatory and canactivate microglia to releaseneurotoxic factors [29], althoughelevations of of pro-inflammatorycytokines when found in AD are smallin comparison to a microbial challengeand under control of chronicinflammation within the CNS by meansof TGFβ1 and IL-10. Clinical studieshave suggested an associationbetween peripheral blood indicators ofsystemic inflammation and thesubsequent development of AD [30].
[29] Conductier G, Blondeau N, Guyon A, Nahon JL, Rovére C. The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol. 2010;244(1):93-100. [30] Holmes C, Butchart J. Systemic inflammation and Alzheimer's disease. Biochem Soc Trans. 2011;39(4):898-901.
Immune system response
Protein-lipid complex remodeling
Lipid process
Immune response
Expression of MHC II is found atincreased levels on the surface ofmicroglia cells in AD in comparisonwith that of control brain tissue [19].Macrophages have been observed toclear Aβ plaque deposits, althoughmacrophages derived from ADpatients have shown defects inintracellular signaling, transport of Aβinto endosomes and completeclearance of Aβ peptides [20].
[19] Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR, et al. Evaluation of the safety and immunogenecity of synthetic Abeta42 (AN1792) in patients with AD. Neurology. 2005;64(1):94-101. [20] Feng Y, Li L, Sun XH. Monocytes and Alzheimer's disease. Neurosci Bull. 2011;27(2):115-122.
Humoral immune response
A decresase of anti-Aβ antibodies inAD patients has been observed incomparison to healthy age-matchedcontrols [26,27,28].
[26] Du Y, Dodel R, Hampel H, Buerger K, Lin S, et al. Reduced levels of amyloid beta-peptide antibody in Alzheimer disease. Neurology. 2011;57(5):801-805. [27] Moir RD, Tseitlin KA, Soscia S, Hyman BT, Irizarry MC, Tanzi RE. Autoantibodies to redox-modified oligomeric Abeta are attenuated in the plasma of Alzheimer's disease patients. J Biol Chem. 2005;280(17):17458-17463. [28] Weksler ME, Relkin N, Turkenich R, LaRusse S, Zhou L, Szabo P. Patients with Alzheimer's disease have lower levels of serum anti-amyloid peptide antibodies than healthy elderly individuals. Exp Gerontol. 2002;37(7):943-948.
Negative regulation of immune effector process
A significantly decreased function ofsuppressor and helper T-cells andnatural killer cells in AD patients hasbeen observed. An impairment ofprotective immune responses toharmful amyloidogenic substancesmay favor their accumulation in thebrain [38].
[38] Xue SR, Xu DH, Yang XX, Dong WL. Alterations in lymphocyte subset patterns and co-stimulatory molecules in patients with Alzheimer disease. Chin Med J (Engl). 2009;122(12):1469-72.
T-helper 1 type immune response; Susceptibility to
T cell mediated Susceptibility to T cell mediated cytotoxicity
Immune system response
CD4+ and CD8+ T cells showincreased reactivity in AD [39].
[39] Schindowski K, Eckert A, Peters J, Gorriz C, Schramm U, et al. Increased T-cell Reactivity and Elevated Levels of CD8+ Memory T-cells in Alzheimer's Disease-patients and T-cell Hyporeactivity in an Alzheimer's Disease-mouse Model: Implications for Immunotherapy. Neuromolecular Med. 2007;9(4):340-54.
Lymphocyte mediated immunity
Regulation of complement activation
Complement activation, classical pathway
The complement system is stronglyactivated in AD and could participate in either the amelioration orenhancement of the pathology. FibrillarAβ is a strong stimulator of thecomplement system [31], and canactivate the classical [32, 33] andalternative [34,35] pathways.Hyperphosphorylated tau contained inneurons can also activate the classicalcomplement cascade [36,37].
[31] Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, et al. Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci USA. 1992;89(21):10016-10020. [32] Afagh A, Cummings BJ, Cribbs DH, Cotman CW, Tenner AJ. Localization and cell association of C1q in Alzheimer's disease brain. Exp Neurol. 1996;138(1):22-32. [33] Chen S, Frederickson RC, Brunden KR. Neuroglial-mediated immunoinflammatory resposnes in Alzheimer's disease: complement activation and therapeutic approaches. Neurobiol Aging. 1996;17(5):781-787. [34] Bradt BM, Kolb WP, Cooper NR. Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide. J Exp Med. 1998;188(3):431-438. [35] Strohmeyer R, Shen Y, Rogers J. Detection of complement alternative pathway mRNA and proteins in the Alzheimer's disease brain. Brain Res Mol Brain Res. 2000;81(1-2):7-18. [36] McGeer PL, Akiyama H, Itagaki S, McGeer EG. Immune system response in Alzheimer's disease. Can J Neurol Sci. 1989;16(4 Suppl):516-527. [37] Shen Y, Lue L, Yang L, Roher A, Kuo Y, et al. Complement activation by neurofibrillary tangles in Alzheimer's disease. Neurosci Lett. 2001;305(3):165-168.
Disease genes & KEGG pathway
Gene Symbol
Number of protein
interactors
Expected Frequency of Interactions
FDR of Observed Gene Lists
FDR of Observed
Relationships
Bottleneck Score Hub Score
DGKQ 5 79 0 0 0.2521 0.1827DLG2 2 97 0 0 0.5802 0.5987DSG3 1 324 0 0 0.8038 0.8765
CCDC62 2 427 0 0 0.2447 0.4229GRIN2A 1 190 0 0 0.1282 0.311APBB1 1 281 0.5 0.5 0.0887 0.2184GRIN2B 1 307 0.33 0.33 0.0471 0.2456
HSD17B10 1 412 0.5 0.5 0.1557 0.211LPL 1 430 0.4 0.4 0.1119 0.1667
PLCB4 1 664 0.5 0.66 0.2931 0.0917PLCB3 1 749 0.57 0.71 0.2218 0.0839PLCB1 1 892 0.63 0.63 0.0262 0.0558PLCB2 1 919 0.55 0.66 0.1166 0.0665CASP3 1 1465 0.6 0.6 0.0011 0.0118
CASP3 2 170 0 0 0.0011 0.0118SNCA 1 564 0.5 0.33 0.0291 0.1764DSG3 1 258 0 0 0.8038 0.8765MAPT 2 4094 1.5 1.66 0.013 0.1109
FADS1 1 2227 5 16 - -TNFSF11 1 3423 5 13 - -
MUC1 1 3839 4 10 - -MAP3K7IP1 2 4857 3.5 6.8 - -
IL23R 1 7033 3.6 7.17 - -IL12B 1 8771 3.5 7 - -STAT3 2 9095 3.14 5.55 - -IL2RA 2 9126 2.75 4.54 - -
SMAD3 2 9139 2.44 3.85 - -TYK2 1 9782 2.3 3.71 - -JAK2 1 9989 2.09 3.47 - -
PLCE1 7 102 0 0 - -ETS2 3 170 0 0 - -
DUSP10 2 516 0.66 0.5 - -SCARB1 1 1688 2 1.69 - -IL1RAP 1 2685 2.2 2.36 - -CDH1 3 2987 2.17 2.18 - -NR5A2 1 3768 2.43 2.44 - -PARK2 1 4093 2.25 2.53 - -
INS 3 4293 2.22 2.27 - -MAGED1 1 4410 2.1 2.26 - -
TH 1 4650 2 2.25 - -MAP3K1 3 4723 1.92 2.04 - -ITGA6 2 5500 1.92 2.03 - -ESR1 3 5738 1.86 1.88 - -MYC 3 5920 1.8 1.8 - -TERT 2
6698
1.88 1.81 - -LAMA5 2 6707 1.76 1.74 - -ALDH2 1 9053 2.11 2 - -PSMA4 1 9438 2.11 2 - -CCND1 1 9874 2 1.95 - -
Parkinson's genes & Alzheimer's pathway
Parkinson's genes & Parkinson's pathway
Crohn's genes & Parkinson's pathway
Carcinoma genes & Alzheimer's pathway
Supplementary Table S6. Parkinson’s disease overlap through protein interactions of disease genes and KEGG pathway networks. We further extend our forward phenomics approach to higher, disease-level traits by examining protein-protein interaction overlap between known Alzheimer’s and Parkinson’s disease genes from KEGG. We chose Parkinson’s due to its similar phenotype as a neurodegenerative disease and that individuals with Parkinson’s have a four to six-fold increased risk for developing Alzheimer’s. As expected, we found that Parkinson’s GWAS host genes interact significantly with those of the Parkinson’s KEGG pathway and those of the Alzheimer’s KEGG pathway (SPAN analysis FDR<5%, 10 edges and 4 genes prioritized for the latter). Two negative control studies consisting of GWAS genes from traits pathologically unrelated to Alzheimer’s disease such as Crohn’s disease (n=9-0) and epithelial cancers (n=184) are presented, and no significant interactions are observed with known AD genes.
AD GeneAD KEGG pathway
genes & first degree interaction partners
Edgetic p-value GO-BP Biomodule of AD
APP APOE 0.0081APP CDK5 0.0075APP LRP1 0.0076APP LRP1B 0.0009APP MAPK8IP1 0.0052APP PRNP 0.011APP SNCA 0.0137
APOC1 APOA2 0.0007APOE APOA2 0.0063APOE APOA4 0.0013APOE APOB 0.0013APOE APOC2 0.0007APOE APOC3 0.0029APOE APOC4 0.0014APOE APP 0.0081APOE LDLR 0.0008APOE LRP1 0.0018APOE LRP2 0.0013APOE LRP8 0.0023APOE PLTP 0.0015APOE SCARB1 0.0014APOE VLDLR 0.004APP ACHE 0.0028
Supplementary Table S7. "Extended GO-BP-Constained" Network ofIndirect Protein Interactions between AD KEGG pathway genes andGenetic Inheritance of AD. Prioritized edges with p<0.05 (unadjusted p-valueof gene pair using empirical distribution from 10,000 permutation resamplings)within protein-protein interaction network connecting AD GWAS and OMIMgenes to genes and first interactors (STRING) from the KEGG Alzheimer'sdisease pathway (hsa05010) within four biomodules of GO biologicalprocesses found to be enriched in AD genes. This network is constructed in asimilar way to that of Supplementary Table S8 with the exception that moreprotein interactions are added here if their interacting genes are bothsubsumed by inheritance in GO into the GO-BP moduels associated to AD inFigure 2. This network is illustrated in corresponds to a subset of the onepresented in Figure 5. Of 103 interactions subsumed under AD-associated GO-BP, 750 met a SPAN network model of p<5% presented here, among 856overall interactions identified between the AD KEGG pathways and theinheritable genes (single or complex).
Localization & Membrane Regulation
PICALM AP2A1 0.0045PICALM AP2M1 0.0031PICALM DNM1 0.0054PICALM EPN1 0.0025PICALM SYNJ1 0.0045PRNP APLP1 0.0003PRNP APP 0.011PRNP CAV1 0.0074PRNP LRP1 0.0085SNCA APP 0.0137SNCA SLC6A3 0.0003APP APBB1 0.0086APP APOE 0.0081APP CASP3 0.0477APP CDK5 0.0075APP CNP 0.0022APP HTRA2 0.0032APP MAPK8 0.0732APP MAPK9 0.0249APP NGFR 0.016APP NUMBL 0.0008APP TGFB1 0.0165
APOE APP 0.0081APP ACHE 0.0028
PICALM PPP3CA 0.0039PLAU SERPINE1 0.0023
PSEN1 DLL1 0.0292PSEN1 GPSM3 0.005PSEN1 NOTCH1 0.017PSEN1 NOTCH2 0.0086PSEN1 NOTCH3 0.0093PSEN1 NOTCH4 0.0053VEGFA ACTA1 0.0368APOC1 APOA1 0.001APOC1 APOA2 0.0007APOE APOA1 0.0101APOE APOA2 0.0063APOE APOA4 0.0013APOE APOB 0.0013APOE APOC2 0.0007APOE APOC3 0.0029APOE SCARB1 0.0014
Localization & Membrane Regulation
Neuronal Process
Lipid Process
A2M APOE 0.0107APOE A2M 0.0107PLAU F2 0.0037PLAU PLAT 0.0074PRNP BCL2 0.0155PRNP HSPD1 0.0016PSEN1 APH1A 0.0069PSEN1 APH1B 0.0053PSEN1 BACE1 0.0027PSEN1 CDH1 0.0227PSEN1 DLL1 0.0292PSEN1 GPSM3 0.005PSEN1 NCSTN 0.011PSEN1 NOTCH1 0.017PSEN1 NOTCH2 0.0086PSEN1 NOTCH3 0.0093PSEN1 NOTCH4 0.0053PSEN1 PSEN2 0.0197PSEN1 PSENEN 0.0076PSEN2 APH1A 0.0033PSEN2 APH1B 0.0066PSEN2 CAPN1 0.0014PSEN2 CASP1 0.0134PSEN2 CASP3 0.0434PSEN2 CASP6 0.0143PSEN2 CASP7 0.0142PSEN2 CASP8 0.0204PSEN2 CFLAR 0.0097PSEN2 GPSM3 0.0018PSEN2 NCSTN 0.0073PSEN2 NOTCH1 0.0056PSEN2 NOTCH2 0.0093PSEN2 NOTCH3 0.0067PSEN2 NOTCH4 0.0019PSEN2 PSEN1 0.0197PSEN2 PSENEN 0.0102
Immune System Process
AD GeneAD KEGG pathway
genes & first degree interaction partners
Edgetic p-value Shared GOID GO biological process
PSEN1 APH1A 0.0007PSEN1 APH1B 0.0007PSEN1 DLL1 0.0007PSEN1 NCSTN 0.001PSEN1 NOTCH1 0.001PSEN1 NOTCH2 0.0013PSEN1 NOTCH3 0.0013PSEN1 NOTCH4 0.0013PSEN1 PSEN2 0.0014PSEN1 PSENEN 0.0019PSEN2 APH1A 0.0029PSEN2 APH1B 0.0033PSEN2 NCSTN 0.0053PSEN2 NOTCH1 0.0053PSEN2 NOTCH2 0.0056PSEN2 NOTCH3 0.0063PSEN2 NOTCH4 0.0063PSEN2 PSEN1 0.0063PSEN2 PSENEN 0.0066APOC1 APOA1 0.0067APOC1 APOA2 0.0069APOE APOA1 0.0073APOE APOA2 0.0076APOE APOA4 0.0086
Notch receptor processing
positive regulation of cholesterol esterification
Supplementary Table S8. "GO-BP Mechanism-Constrained" Network of IndirectProtein Interactions between AD KEGG pathway genes and Genetic Inheritance ofAD (see Figure 5, AD OMIM genes and AD-associated host genes of GWAS SNPs).Prioritized edges with p<0.03 (unadjusted p-value of gene pair using empirical distriubtionfrom 10,000 permutation resamplings) within SPAN-prioritized protein-protein interactionnetwork connecting AD GWAS and OMIM genes to genes and first interactors (STRING)of the KEGG Alzheimer's disease pathway (hsa05010) containing shared AD-associatedGO biological processes enriched in AD genes (identical shared GO term for theinteractor protein and the genetic inheritance protein). The AD associations to GO-BPwere identified in Figure 2 as common between GWAS genes and OMIM genes. Hereeach protein interaction for which the 36 interacting gene pairs were both in the same GO-BP processand also significant in the SPAN protein interaction network modeling (p<0.03)among 856 interactions identified are shown.
GO:0007220
GO:0010873
APOE APOA2 0.0093APOE APOB 0.0093
APOC1 APOA1 0.0101APOC1 APOA2 0.0101APOE APOA1 0.0102APOE APOA2 0.011APOE APOA4 0.017APOE APOC3 0.0197APOE SCARB1 0.0197
APOC1 APOA2 0.0197 GO:0050995 negative regulation of lipid catabolic process
PSEN1 PSEN2 0.0197PSEN2 PSEN1 0.0292
GO:0051605
low-density lipoprotein particle remodeling
high-density lipoprotein particle remodeling
protein processing
GO:0034374
GO:0034375
Random Permutation (Mean frequency at 95% confidence interval)
40 AD Gene List Permutation (Mean frequency at 95% confidence interval)
40 AD Gene List: Priortized Mechanisms (Count)
GO Biological Processes 261 666 59
(Tables S3 and S4)
Protein-Protein Interactions 812 665 72
(Figure 3)
Supplementary Table S9. Reduction of dimenstionality in GO biological processesand protein-protein interactions of 40 AD genes. Of the 40 single gene and complexinheritance genes associated to Alzheimer’s, 32 have Entrez Gene IDs that could bemapped to GO biological process IDs. Random samples of 32 genes from the GOdatabase including 17,871 genes were permutated 10,000 times, and the correspondingmean frequency of associated GO biological processes at the 95% confidence interval isreported. Of the 40 single and complex inheritance genes associated to Alzheimer’s, 32have Entrez Gene IDs that could be mapped to GO biological process IDs. Of the 40single and complex inheritance genes associated to Alzheimer’s, 28 were connectedthrough protein-protein interaction networks using the STRING database (see Methods). Random samples of 28 genes from the STRING database including 7,681 genes werepermutated 10,000 times, and the corresponding mean frequency of protein interactions atthe 95% confidence interval is reported.