supplementary method s1 - · pdf filesupplementary method s1. ... rs2075650 apoe 19q13.32...

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:


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:


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-


A2M, CYS972TYR rs1800433 missense

.0003ALPHA-2-


A2M, IVS1DEL DEL

.0004ALPHA-2-


A2M, ARG681HIS rs1800434 missense

.0005 ALZHEIMER DISEASE, SUSCEPTIBILITY TO A2M, EX18DEL DEL

.0006ALPHA-2-


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


ASSOCIATED WITH APOE DEFICIENCY

APOE, IVS3AS, A-G, -1

Alternative splicing

Supplementary Table S2. Alzheimer's Disease Intragenic SNPs reported in OMIM.

.0006


ASSOCIATED WITH APOE LEIDEN

APOE, 21-BP INS, DUP

CODONS 121-127

INS

.0007



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


ASSOCIATED WITH APOE DEFICIENCY

APOE, TRP210TER rs121918396 -

.0015 APOE3 ISOFORM APOE, CYS112 AND ARG158 Multiple

.0016 ALZHEIMER DISEASE 2 APOE, CYS112ARG rs429358 missense

.0017


ASSOCIATED WITH APOE DEFICIENCY,

AUTOSOMAL RECESSIVE

APOE, 1-BP DEL, 2919G

DEL, FS60TERDEL

.0018 HYPERLIPOPROTEINEMIA, TYPE III

APOE, ARG145HIS rs121918397 -

.0019


ASSOCIATED WITH APOE2-FUKUOKA

APOE, ARG158CYS

AND ARG224GLN

Multiple

.0020

HYPERCHOLESTEROLEMIA AND

HYPERTRIGLYCERIDEMIA, TYPE III

APOE, GLU3LYS AND

GLU13LYSMultiple

.0021



APOE, ARG158CYS

AND VAL236GLU

Multiple

.0022



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


APP, VAL717PHE rs63750264 -


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)


APP, LYS670ASN

AND MET671LEU

rs63750445 missense


APP, LYS670ASN

AND MET671LEU

rs63751263 missense


APP, ALA713THR rs63750066 coding-

synon,missense


APP, GLU665ASP rs63750363 missense


APP, ILE716VAL rs63750399 coding-

synon,missense


APP, VAL715MET rs63750734 coding-

synon,missense


APP, GLU693GLY rs63751039 missense

.0014

CEREBRAL AMYLOID ANGIOPATHY, APP-RELATED, ITALIAN

VARIANT

APP, GLU693LYS rs63750579 missense,untrans

lated-3


APP, THR714ILE rs63750973 missense

.0016

CEREBRAL AMYLOID ANGIOPATHY, APP-

RELATED, IOWA VARIANT

APP, ASN694ASP

Allelic Variant(.0016)


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


APP, VAL717LEU


.0022

DEMENTIA, EARLY-ONSET PROGRESSIVE,

AUTOSOMAL RECESSIVE

APP, ALA673VAL


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


MPO, TYR173CYS rs78950939 missense


MPO, MET251THR rs56378716 missense


MPO, 14-BP DEL DEL


MPO, ALA332VAL rs28730837 missense


MPO, LEU572TRP rs119469012 missense


MPO, IVS11AS, A-C, -2, 109-BP

DELDEL

.0008 ALZHEIMER DISEASE, SUSCEPTIBILITY TO MPO, -463G-A Allelic

Variant(.0008)


MPO, GLY501SER rs119469013 missense


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


PRNP, ALA117VAL rs74315402 missense


EARLY-ONSET, SUSCEPTIBILITY TO,

PRNP, MET129VAL rs1799990 missense


PRNP, GLU200LYS rs28933385 missense


PRNP, ASP178ASN

AND MET129VAL

rs1799990 missense


PRNP, ASP178ASN

AND MET129VAL

rs74315403 missense

.0010 FATAL FAMILIAL INSOMNIA

PRNP, ASP178ASN AND MET129

rs74315403 missense


PRNP, PHE198SER rs74315405 missense


PRNP, GLN217ARG rs74315406 missense


PRNP, VAL210ILE rs74315407 missense


PRNP, PRO105LEU rs11538758 missense


PRNP, VAL180ILE rs74315408 missense

.0001 NOS3, GLU298ASP rs1799983 missense


PRNP, MET232ARG rs74315409 missense

.0018

SPONGIFORM ENCEPHALOPATHY

WITH NEUROPSYCHIATRIC

FEATURES

PRNP, ASN171SER rs16990018 missense

.0019CREUTZFELDT-JAKOB

DISEASE, PROTECTION AGAINST

PRNP, GLU219LYS rs1800014 missense


PRNP, GLY131VAL rs74315410 missense

.0022



FEATURES

PRNP, THR183ALA rs74315411 missense


PRNP, ARG208HIS rs74315412 missense


PRNP, HIS187ARG rs74315413 missense

.0025



FEATURES

PRNP, PRO105THR rs74315414 missense


PRNP, ALA133VAL rs74315415 missense


PRNP, PRO105SER rs74315414 missense

.0028 KURU, PROTECTION AGAINST

PRNP, GLY127VAL


PSEN1 *104311 14q24.3


PSEN1, MET146LEU rs63750306 missense


PSEN1, HIS163ARG rs63750590 missense


PSEN1, ALA246GLU rs63750526 missense


PSEN1, LEU286VAL rs63751235 missense


PSEN1, CYS410TYR rs661 missense


PSEN1, MET139VAL rs63751037 missense


PSEN1, MET146VAL rs63750306 -


PSEN1, HIS163TYR rs63749885 missense


PSEN1, GLU280ALA rs63750231 missense


PSEN1, GLU280GLY rs63750231 -


PSEN1, PRO267SER rs63751229 missense


PSEN1, IVS8AS, G-T, -

1, EX9DELDEL


PSEN1, GLU120ASP rs63751272 missense


PSEN1, ALA426PRO rs63751223 missense


PSEN1, MET146ILE rs63750391 missense


PSEN1, LEU250SER rs63751163 missense

.0017

ALZHEIMER DISEASE, FAMILIAL, WITH

SPASTIC PARAPARESIS AND UNUSUAL PLAQUES

PSEN1, ARG278THR rs63749891 missense


PSEN1, IVS4DS, 1-BP

DEL, GDEL


PSEN1, 1548GC-TG Multiple


PSEN1, CYS92SER rs63751141 missense


PSEN1, GLY206ALA rs63750082 missense

.0022

ALZHEIMER DISEASE, FAMILIAL, 3, WITH

SPASTIC PARAPARESIS AND

APRAXIA

PSEN1, GLY266SER


.0023 DEMENTIA, FRONTOTEMPORAL

PSEN1, LEU113PRO rs63751399 missense




PSEN1, LEU174MET rs63751144 missense


FAMILIAL, 3, WITH UNUSUAL PLAQUES

PSEN1, LEU271VAL rs63750886 missense

.0027 PICK DISEASE OF BRAIN

PSEN1, GLY183VAL rs63751068 missense


PSEN1, PRO436GLN


.0029



PSEN1, 6-BP INS, NT715 INS


PSEN1, ARG278ILE rs63749891 missense

.0031


SPASTIC PARAPARESIS AND

APRAXIA


.0032



PSEN1, 3-BP DEL DEL


PSEN1, ALA431GLU rs63750083 missense

.0034 CARDIOMYOPATHY, DILATED, 1U

PSEN1, ASP333GLY Allelic Variant()


PSEN1, ALA79VAL rs63749824 missense


PSEN1, SER170PHE rs63750577 missense


FAMILIAL, 3, WITH UNUSUAL PLAQUES

PSEN1, GLY217ARG


.0038 ACNE INVERSA, FAMILIAL, 3

PSEN1, 1-BP DEL, 725C DEL

PSEN2 *600759 1q31-q42


PSEN2, ASN141ILE rs63750215 missense


PSEN2, MET239VAL rs28936379 missense


PSEN2, ASP439ALA rs63750110 missense


PSEN2, THR430MET rs63750666 missense


PSEN2, THR122PRO rs63749851 missense


PSEN2, MET239ILE rs63749884 missense


PSEN2, THR122ARG


.0008 CARDIOMYOPATHY, DILATED, 1V

PSEN2, SER130LEU rs63750197 missense


PSEN2, ALA85VAL rs63750048 missense

SNCA *163890 4q21

.0001PARKINSON DISEASE 1,

AUTOSOMAL DOMINANT

SNCA, ALA53THR rs104893877 missense


AUTOSOMAL DOMINANT

SNCA, ALA30PRO rs104893878 missense


AUTOSOMAL DOMINANT

SNCA, TRIPLICATION TRP

.0004 DEMENTIA, LEWY BODY

SNCA, GLU46LYS rs104893875 missense


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


.0002 TNF RECEPTOR BINDING, ALTERED

TNF, ARG32TRP


.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


phosphatidylcholine catabolic process

96% 1 0.02411578 1 APOC1


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.

supplementary method s1 - · pdf filesupplementary method s1. ... rs2075650 apoe 19q13.32...

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