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Table 1 Genome-wide significant AD-associated genes with potential roles in innate and adaptive immunity

From: The neuroimmune axis of Alzheimer’s disease

Chr

Gene

Immune-related function

References

1

ADAMTS4

Immunomodulator

Jansen et al., 2019 [22]; Redondo-García et al., 2021 [23]

1

AGRN

Survival and function of monocytes

Mazzon et al., 2012 [24]

1

CR1

Immunity—e.g., microglial phagocytosis and clearance of complement opsonized molecules

Lambert et al., 2009 [25]; Borucki et al., 2020 [26]

1

PSEN2

Innate immune system

Agrawal et al., 2016 [27]; Nam et al., 2022 [28]; Fung et al., 2020 [29]; Mendez et al., 2017 [30]

1

SORT1

Monocytes and T cells

Bellenguez et al., 2022 [31]; Herda et al., 2012 [32]; Mortensen et al., 2014 [33]

2

ADAM17

T cell response

Lambrecht et al., 2018 [34]

2

BIN1

Pro-inflammatory response; endocytosis and phagocytosis

Seshadri et al., 2010 [35], Sudwarts et al., 2022 [36]

2

FHL2

Wound healing and inflammation

Nordhoff et al., 2012 [37]; Wixler et al., 2019 [38]

2

INPP5D

Immunity and microglia function

Efthymiou and Goate, 2017 [19]; Lambert et al., 2013 [39]

2

SPRED2

NK cells; cytokine/chemokine production

Itakura et al., 2017 [40]

2

PRKD3

Thymic selection during T cell development

Ishikawa et al., 2016 [41]

3

IL17RD

Cytokines

Brigas et al., 2021 [42]; Girondel et al., 2021 [43]

3

MME

Neutrophils

Schulte-Schrepping et al., 2020 [44]

4

CLNK

Immune cell-specific adaptors

Utting et al., 2004 [45]

4

RHOH

TCR signaling

Gu et al., 2006 [46]

4

SCARB2

IFN-I production and cholesterol regulation

Guo et al., 2015 [47]; Heybrock et al., 2019 [48]

5

APC

T cell migration

Mastrogiovanni et al., 2022 [49]

5

HAVCR2

Viral receptor; T cells

Zhai et al., 2021 [50]; Wightman et al., 2021 [51]

5

HBEGF

T cells

Macdonald et al., 2021 [52]

5

MEF2C

B cell proliferation, regulate microglia, and antigen presentation

Sao et al., 2018 [53]

5

PFDN1/HBEGF

Macrophage-mediated cellular proliferation

Higashiyama et al., 1991 [54]

5

RASGEF1C

Macrophages; microglia

Srinivasan et al., 2020 [55]

5

TNIP1

NF-κB regulation

G'Sell et al., 2016 [56]; Gurevich et al., 2011 [57]

6

CD2AP

T lymphocyte

Raju et al., 2018 [58]; Tao et al., 2019 [59]

6

HLA-DRB5/

HLA-DRB1

Immunity—e.g., antigen presentation

Lambert et al., 2013 [39]; Lu et al., 2017 [60]

6

TREM2

Phagocytosis, and cellular metabolism in myeloid cells, microglia activation as well as binding to Aβ

Griciuc et al., 2019 [61]; Guerreiro et al., 2013 [13]; Jonsson et al., 2013 [14]; Kunkle et al., 2019 [62]; Bis et al., 2020 [63]; Sims et al., 2017 [64]

7

EPHA1

Immunity, BBB permeability, and immune cell trafficking

Ivanov et al., 2006 [65]; Chen et al., 2018 [66]

7

IKZF1

T/B cell dysregulation

Hoshino et al., 2022 [67]

7

PILRA

Immunoglobulin receptor; viral receptor

Agostini et al., 2019 [68]

7

SEC61G

Antigen presentation

Zehner et al., 2015 [69]

7

TMEM106B

Innate immune system

Rhinn et al., 2017 [70]

8

CLU

Immunity, binding to Aβ, and inhibition of complement system

Tschopp et al., 1993 [71]; Lambert et al., 2009 [25]; Zhao et al., 2015 [72]

8

CTSB

Immune cell infiltration

Ma et al., 2022 [73]; Ha et al., 2008 [74]

8

PTK2B

Spreading, migration, and function of immune cells

Okigaki et al., 2003 [75]; Lambert et al., 2013 [39]

8

SHARPIN

Neuroinflammation and NF-κB activation

Asanomi et al., 2019 [76]

9

ABCA1

Immune modulation; myeloid cells; dendritic cells

Zamanian-Daryoush et al., 2017 [77]; Westerterp et al., 2017 [78]

10

BLNK

B cell linker

Fu et al., 1998 [79]; Han et al., 2016 [80]

10

ECHDC3

NK, monocyte differentiation, cell infiltration

Zhao et al., 2022 [81]

10

TSPAN14

Mast cell function

Orinska et al., 2020 [82]

11

MS4A

Expressed in immune cells, TREM2 regulation, phagocytosis, regulation of complement system

Deming et al., 2019 [83]; Kuek et al., 2016 [84]

11

PICALM

Endocytosis and Aβ clearance

Zhao et al., 2015 [72]; Harold et al., 2009 [85]

11

SORL1

Microglia, monocyte migration, pro-inflammatory cytokines regulation and phagocytosis

Talbot et al., 2018 [86]; Knupp et al., 2020 [87]

11

SPI1

PU.1, altered microglia function

Jones et al., 2021 [88]

12

TPCN1

Antigen-presenting cells

He et al., 2020 [89]

14

FERMT2

Immune cell infiltration

Su et al., 2021 [90]

14

IGHG1

Antigen and immunoglobulin receptor binding activity

Lekhraj et al., 2022 [91]

14

PSEN1

Microglial hyperactivation

Lee et al., 2002 [92]

15

ADAM10

Immune cell function

Lambrecht et al., 2018 [34]

15

CTSH

Autoimmune inflammation, macrophages and phagocytosis, cytokines

Faraco et al., 2013 [93]; Conus et al., 2010 [94]; Zavašnik-Bergant et al., 2004 [95], Li et al., 2010 [96]

15

IGF1R

Stimulates regulatory T cells, autoimmunity

Bilbao et al., 2014 [97]; Andersson et al., 2018 [98]

15

RORA

Inflammatory response; lymphoid cell development; T cell survival; autoimmunity and chronic inflammatory response

Oh et al., 2019 [99]; Lo et al., 2016 [100]; Chi et al., 2021 [101]; Wang et al., 2021 [102]

15

SPPL2A

Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF-α

Fluhrer et al., 2006 [103]

16

IL34

Proliferation, survival and differentiation of monocytes and macrophages

Foucher et al., 2013 [104]; Lin et al., 2008 [105]

16

KAT8

Viral immunity

Huai et al., 2019 [106]

16

MAF

Regulates IL-10

Gabryšová et al., 2018 [107]

16

PLCG2

Involved in multiple pathways in immune cells

Sims et al., 2017 [64]; Magno et al., 2021 [108]

16

ZNF423

B cell differentiation

Harder et al., 2013 [109]

17

ABI3

Immunity, regulation of actin polymerization, and microglia function

Sims et al., 2017 [64]; Satoh et al., 2017 [110]

17

ACE

Innate and adaptive immune system

Bernstein et al., 2018 [111]

17

SCIMP

MHC class II signaling transduction

Draber et al., 2011 [112]

17

TSPOAP1

Microglia-associated gene; IFN signaling

Bhatt et al., 2020 [113]

19

ABCA7

Microglia Aβ clearance and cholesterol metabolism

Hollingworth et al., 2011 [11]; Kim et al., 2006 [114]; Steinberg et al., 2015 [115]

19

APOE

Lipid metabolism; T cell activation

Saunders et al., 1993 [116]; Bonacina et al., 2018 [117]

19

CD33

Immunity, phagocytosis, and transmembrane receptor in myeloid cells

Bertram et al., 2008 [10]; Griciuc et al., 2013 [118]; Griciuc et al., 2019 [61]; Crocker et al., 2007 [119]

19

LILRB2

Immunoglobulin-like receptor; influence immune activation

Deng et al., 2021 [120]

20

RBCK1

Immunodeficiency disorders; LUBAC inhibits TNF-α signaling, dousing inflammation

Boisson et al., 2012 [121]; Bellenguez et al., 2022 [31]

20

CASS4

Eosinophil asthma response

Esnault et al., 2013 [122]

21

ADAMTS1

Immunomodulator

Rodríguez-Baena et al., 2018 [123]; Kunkle et al., 2019 [62]

21

APP

Antimicrobial peptide

Kumar et al., 2016 [124]; Eimer et al., 2018 [125]; Jonsson et al., 2012 [126]

  1. The selected genes were implicated based on independent genetic loci with genome-wide significance in at least one GWAS in AD [12, 22, 25, 31, 39, 51, 85, 127,128,129,130] and a potential role in the immune system. IFN-I type I interferon; NK cell natural killer cell; TCR T cell receptor; MHC major histocompatibility complex; NF-κB nuclear factor kappa B; LUBAC linear ubiquitination assembly complex