SORL1

Summary

SORL1 (sortilin related receptor 1, HGNC:11185) is a protein-coding gene on chromosome 11q24.1, encoding Sortilin-related receptor (Q92673). Sorting receptor that directs several proteins to their correct location within the cell.

This gene encodes a mosaic protein that belongs to at least two families: the vacuolar protein sorting 10 (VPS10) domain-containing receptor family, and the low density lipoprotein receptor (LDLR) family. The encoded protein also contains fibronectin type III repeats and an epidermal growth factor repeat. The encoded preproprotein is proteolytically processed to generate the mature receptor, which likely plays roles in endocytosis and sorting. Mutations in this gene may be associated with Alzheimer’s disease.

Source: NCBI Gene 6653 — RefSeq curated summary.

At a glance

• Gene–disease (curated): early-onset autosomal dominant Alzheimer disease (Supportive, GenCC)
• GWAS associations: 33
• Clinical variants (ClinVar): 912 total — 18 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 26
• MANE Select transcript: NM_003105

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11185
Approved symbol	SORL1
Name	sortilin related receptor 1
Location	11q24.1
Locus type	gene with protein product
Status	Approved
Aliases	gp250, LR11, LRP9, SorLA, SorLA-1
Ensembl gene	ENSG00000137642
Ensembl biotype	protein_coding
OMIM	602005
Entrez	6653

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 7 protein_coding, 7 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000260197, ENST00000524633, ENST00000524873, ENST00000525532, ENST00000527649, ENST00000527934, ENST00000528339, ENST00000529445, ENST00000530365, ENST00000532451, ENST00000532694, ENST00000534286, ENST00000534754, ENST00000905166, ENST00000905167

RefSeq mRNA: 1 — MANE Select: NM_003105 NM_003105

CCDS: CCDS8436

Canonical transcript exons

ENST00000260197 — 48 exons

Exon	Start	End
ENSE00000532819	121559519	121559657
ENSE00000532821	121570157	121570270
ENSE00000748901	121574241	121574363
ENSE00000991343	121549960	121550088
ENSE00000991344	121550585	121550670
ENSE00000991345	121553937	121554109
ENSE00000991346	121555187	121555318
ENSE00000991347	121583458	121583583
ENSE00000991348	121586222	121586329
ENSE00000991349	121588020	121588151
ENSE00000991350	121589259	121589390
ENSE00000991351	121590040	121590174
ENSE00000991352	121591001	121591156
ENSE00000991353	121595623	121595772
ENSE00000991354	121604193	121604324
ENSE00000991355	121605113	121605239
ENSE00000991356	121605402	121605571
ENSE00000991357	121606845	121606957
ENSE00000991358	121607186	121607290
ENSE00000991359	121608104	121608176
ENSE00000991360	121611076	121611158
ENSE00000991366	121622162	121622268
ENSE00001100819	121625085	121625277
ENSE00001134458	121452314	121452616
ENSE00001283790	121627555	121627767
ENSE00001314697	121629496	121633763
ENSE00003463287	121532464	121532552
ENSE00003463448	121557314	121557405
ENSE00003478901	121478118	121478243
ENSE00003493761	121621064	121621238
ENSE00003504410	121577281	121577400
ENSE00003514996	121490043	121490110
ENSE00003515953	121612736	121612832
ENSE00003520049	121618774	121618893
ENSE00003533314	121514152	121514321
ENSE00003533392	121566940	121567113
ENSE00003541672	121619753	121619917
ENSE00003546837	121558591	121558837
ENSE00003548278	121522916	121522989
ENSE00003571739	121513003	121513104
ENSE00003582072	121522586	121522703
ENSE00003585013	121520657	121520849
ENSE00003602900	121614871	121615055
ENSE00003606568	121496869	121497049
ENSE00003615663	121545243	121545429
ENSE00003641851	121488032	121488193
ENSE00003650386	121543548	121543726
ENSE00003683621	121470007	121470123

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.8826 / max 1413.1069, expressed in 1046 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117200	27.7920	1029
117201	0.7636	258
117203	0.5961	244
117199	0.5874	243
117228	0.4479	155
117222	0.3894	54
117217	0.3188	111
117229	0.2513	110
117204	0.2394	59
117202	0.2298	125

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
frontal pole	UBERON:0002795	99.38	gold quality
paraflocculus	UBERON:0005351	99.37	gold quality
middle frontal gyrus	UBERON:0002702	99.32	gold quality
inferior vagus X ganglion	UBERON:0005363	99.23	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.15	gold quality
middle temporal gyrus	UBERON:0002771	99.06	gold quality
endothelial cell	CL:0000115	98.95	gold quality
subthalamic nucleus	UBERON:0001906	98.90	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.89	gold quality
postcentral gyrus	UBERON:0002581	98.80	gold quality
parietal lobe	UBERON:0001872	98.74	gold quality
superior vestibular nucleus	UBERON:0007227	98.70	gold quality
ventral tegmental area	UBERON:0002691	98.66	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.58	gold quality
CA1 field of hippocampus	UBERON:0003881	98.53	gold quality
pons	UBERON:0000988	98.47	gold quality
lateral globus pallidus	UBERON:0002476	98.45	gold quality
blood	UBERON:0000178	98.44	gold quality
medulla oblongata	UBERON:0001896	98.43	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.35	gold quality
substantia nigra pars compacta	UBERON:0001965	98.16	gold quality
entorhinal cortex	UBERON:0002728	98.14	gold quality
corpus callosum	UBERON:0002336	98.07	gold quality
renal medulla	UBERON:0000362	97.98	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.97	gold quality
globus pallidus	UBERON:0001875	97.93	gold quality
orbitofrontal cortex	UBERON:0004167	97.91	gold quality
medial globus pallidus	UBERON:0002477	97.81	gold quality
parotid gland	UBERON:0001831	97.73	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.70	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-ENAD-27	yes	861.03
E-GEOD-81608	yes	822.01
E-MTAB-9067	yes	581.43
E-CURD-6	yes	267.21
E-HCAD-35	yes	37.32
E-MTAB-5061	yes	18.96
E-MTAB-9221	yes	18.48
E-HCAD-25	yes	16.26
E-GEOD-81547	yes	14.19
E-GEOD-83139	yes	13.08
E-MTAB-9801	yes	8.73
E-CURD-114	yes	7.06
E-GEOD-137537	yes	4.76
E-GEOD-150728	no	1226.74
E-CURD-10	no	222.22

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

224 targeting SORL1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-3148	99.97	75.06	6478

Literature-anchored findings (GeneRIF, showing 40)

• sorLA is necessary for head activator signaling and function (PMID:12530537)
• Secretion of soluble LR11 is induced in SMCs during the rapidly proliferating phase, & the secreted LR11 induces the migration activities of SMCs. Both the cell-anchored & secreted forms of LR11 have the capacity to bind to and form complexes with uPAR. (PMID:14764453)
• Low-density lipoprotein receptor expression, relative with 11 binding repeats (LR11), shows dramatic and consistent loss of immunocytochemical staining in histologically normal-appearing neurons in Alzheimer disease brains compared to controls. (PMID:15313836)
• Reduced sorLA expression in the human brain may increase amyloid beta-peptide production and plaque formation and promote spontaneous Alzheimer’s disease. (PMID:16174740)
• SorLA acts as a trafficking receptor that prevents beta-site APP-cleaving enzyme interactions with amyloid precursor protein & hence BACE cleavage of APP. (PMID:16407538)
• analytical ultracentrifugation of recombinant APP and sorLA fragments further narrowed down the binding domains to the cluster of complement-type repeats in sorLA that forms a 1:1 stoichiometric complex with the carbohydrate-linked domain of APP (PMID:16489755)
• SorLA might directly regulate transcription after activation by gamma-secretase (PMID:16531402)
• he sorting protein-related receptor sorLA/LR11 regulates processing and trafficking of the precursor of the amyloid-beta peptides, revealing an alternative target for developing molecular clinical therapeutic compounds for Alzheimer Disease. (PMID:16565469)
• We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease (PMID:17220890)
• Finding of novel SNP and haplotype associations suggests that there may be extensive allelic heterogeneity in SORL1, and broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants. (PMID:17420311)
• Reduction of sortilin-1 in Alzheimer hippocampus . (PMID:17589324)
• Neuronal LR11 levels are reduced in prodomal Alzheimer’s disease(AD). Correlation between LR11 expression and cognition indicates reduced LR11 levels reflect disease severity and may predict progression to AD in subgroup of mild cognitive impairment. (PMID:17721864)
• These findings indicate a modest association of variants in SORL1 with AD. (PMID:17826910)
• One SNP rs2070045 was marginally replicated in the three sample sets combined (nominal P=0.035); however, this result does not remain significant when accounting for multiple comparisons. (PMID:17949987)
• Results of our large case-control whole-genome scan at over 500,000 polymorphisms present weak evidence for association and potentially narrows the association interval. (PMID:17975299)
• There was a significant association between genetic variants of SORL1 protein and autopsy-confirmed Alzheimer disease. (PMID:17978276)
• Our study suggests that certain SORL1 haplotypes at SNPs 19-24 modulated risk of AD in our Chinese population. (PMID:18063222)
• These results provide an independent replication of the association between Alzheimer’s disease and SORL1 (PMID:18090307)
• SORL l are associated with Alzheimer’s disease and releated to the trafficking of Amyloid Protein Precursor in subcellular lever. (PMID:18093545)
• Two signals in distinct regions of SORL1 were shown to be mutually independent, supporting allelic heterogeneity at the SORL1 locus in Belgians. Findings confirm that genetic variants in SORL1 may be important risk factors for late-onset Alzheimer disease (PMID:18407551)
• This study found a SORL1 haplotype which was associated with CSF levels of amyloid-beta cleavage products, measured as altered levels of Abeta42. Thus our data suggest that SORL1 gene variants might influence AD pathology. (PMID:18541377)
• Data show that the analysis of allele, genotype and haplotype frequencies reveals no association of SORL1 SNPs with late-onset Alzheimer’s disease with in a large Caucasian American case-controls cohort. (PMID:18562096)
• apoA-V binds to receptors possessing LDL-A repeats and Vsp10p domains, including SorLA and Sortilin, and apoA-V is internalized into cells via these receptors (PMID:18603531)
• our study failed to detect any association between the single nucleotide polymorhisms and Alzheimer’s disease in Japanese (PMID:18685254)
• 2 clusters of single nucleotide polymorphisms in the SORL1 are causally associated with late-onset Alzheimer’s disease. At the cellular level, SORL1 is involved in intracellular trafficking of amyloid precursor protein. Review. (PMID:18713574)
• This study fail support a regulatory role for SORL1 polymorphisms in mRNA expression. (PMID:18938222)
• Variants of SORL1 associated with AD are also associated with MRI and neuropathological measures of neurodegenerative and cerebrovascular disease. (PMID:19064752)
• In patients with Alzheimer disease as well as those with the amnesic form of mild cognitive impairment, an early stage of Alzheimer disease, the expression of SORL1 is reduced in the brain. (PMID:19364927)
• our data support a role of SORL1 polymorphisms in Alzheimer Disease. (PMID:19368828)
• Genetic variants of SORL1 affect susceptibility to late-onset AD. (PMID:19539718)
• Analysis of single nucleotide polymorphisms in the SORL1 gene finds no association with either Alzheimer’s disease or with cognitive function after adjusting for multiple testing. (PMID:19584446)
• SORL1 has a role in dementia risk in Swedes [meta-analysis] (PMID:19653016)
• Our results confirm the association of SORL1 with Alzheimer disease and show a possible effect of female sex (PMID:19822782)
• the circulating sLR11 might have a role in coronary organic stenosis (PMID:20047743)
• SNPs may play a role in late-onset Alzheimer disease susceptibility among Han Chinese (PMID:20625269)
• These results suggest that the quantification of cerebrospinal fluid sLR11 may serve as a biomarker of Alzheimer disease, although the diagnostic value for individual patients is limited (PMID:20689279)
• A gene association of single nucleotide polymorphisms in SORL1 is found in subjects with dementia of Alzheimer’s disease and Down syndrome. (PMID:20946940)
• overexpression of SorLA increased migration of THP-1 monocytes to monocyte chemoattractant protein-1 with a coincident increase in UPAR expression. (PMID:20970138)
• LR11 is phosphorylated in vivo and indicate that ROCK2 phosphorylation of LR11 may enhance LR11 mediated processing of APP and amyloid production. (PMID:21147781)
• The temporal cortex is more susceptible to Alzheimer’s pathology and demonstrates a 2-fold increase in SORL1-mRNA levels in carriers of the minor alleles at single nucleotide polymorphisms, compared with noncarriers. (PMID:21185108)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sorl1	ENSDARG00000013892
mus_musculus	Sorl1	ENSMUSG00000049313
rattus_norvegicus	Sorl1	ENSRNOG00000064634

Paralogs (4): SORCS1 (ENSG00000108018), SORT1 (ENSG00000134243), SORCS3 (ENSG00000156395), SORCS2 (ENSG00000184985)

Protein

Protein identifiers

Sortilin-related receptor — Q92673 (reviewed: Q92673)

Alternative names: Low-density lipoprotein receptor relative with 11 ligand-binding repeats, SorLA-1, Sorting protein-related receptor containing LDLR class A repeats

All UniProt accessions (5): E9PKB0, E9PP43, E9PPB3, E9PS32, Q92673

UniProt curated annotations — full annotation on UniProt →

Function. Sorting receptor that directs several proteins to their correct location within the cell. Along with AP-1 complex, involved Golgi apparatus - endosome sorting. Sorting receptor for APP, regulating its intracellular trafficking and processing into amyloidogenic-beta peptides. Retains APP in the trans-Golgi network, hence preventing its transit through late endosomes where amyloid beta peptides Abeta40 and Abeta42 are generated. May also sort newly produced amyloid-beta peptides to lysosomes for catabolism. Does not affect APP trafficking from the endoplasmic reticulum to Golgi compartments. Sorting receptor for the BDNF receptor NTRK2/TRKB that facilitates NTRK2 trafficking between synaptic plasma membranes, postsynaptic densities and cell soma, hence positively regulates BDNF signaling by controlling the intracellular location of its receptor. Sorting receptor for GDNF that promotes GDNF regulated, but not constitutive secretion. Sorting receptor for the GDNF-GFRA1 complex, directing it from the cell surface to endosomes. GDNF is then targeted to lysosomes and degraded, while its receptor GFRA1 recycles back to the cell membrane, resulting in a GDNF clearance pathway. The SORL1-GFRA1 complex further targets RET for endocytosis, but not for degradation, affecting GDNF-induced neurotrophic activities. Sorting receptor for ERBB2/HER2. Regulates ERBB2 subcellular distribution by promoting its recycling after internalization from endosomes back to the plasma membrane, hence stimulating phosphoinositide 3-kinase (PI3K)-dependent ERBB2 signaling. In ERBB2-dependent cancer cells, promotes cell proliferation. Sorting receptor for lipoprotein lipase LPL. Promotes LPL localization to endosomes and later to the lysosomes, leading to degradation of newly synthesized LPL. Potential sorting receptor for APOA5, inducing APOA5 internalization to early endosomes, then to late endosomes, wherefrom a portion is sent to lysosomes and degradation, another portion is sorted to the trans-Golgi network. Sorting receptor for the insulin receptor INSR. Promotes recycling of internalized INSR via the Golgi apparatus back to the cell surface, thereby preventing lysosomal INSR catabolism, increasing INSR cell surface expression and strengthening insulin signal reception in adipose tissue. Does not affect INSR internalization. Plays a role in renal ion homeostasis, controlling the phospho-regulation of SLC12A1/NKCC2 by STK39/SPAK kinase and PPP3CB/calcineurin A beta phosphatase, possibly through intracellular sorting of STK39 and PPP3CB. Stimulates, via the N-terminal ectodomain, the proliferation and migration of smooth muscle cells, possibly by increasing cell surface expression of the urokinase receptor uPAR/PLAUR. This may promote extracellular matrix proteolysis and hence facilitate cell migration. By acting on the migration of intimal smooth muscle cells, may accelerate intimal thickening following vascular injury. Promotes adhesion of monocytes. Stimulates proliferation and migration of monocytes/macrophages. Through its action on intimal smooth muscle cells and macrophages, may accelerate intimal thickening and macrophage foam cell formation in the process of atherosclerosis. Regulates hypoxia-enhanced adhesion of hematopoietic stem and progenitor cells to the bone marrow stromal cells via a PLAUR-mediated pathway. This function is mediated by the N-terminal ectodomain. Metabolic regulator, which functions to maintain the adequate balance between lipid storage and oxidation in response to changing environmental conditions, such as temperature and diet. The N-terminal ectodomain negatively regulates adipose tissue energy expenditure, acting through the inhibition the BMP/Smad pathway. May regulate signaling by the heterodimeric neurotrophic cytokine CLCF1-CRLF1 bound to the CNTFR receptor by promoting the endocytosis of the tripartite complex CLCF1-CRLF1-CNTFR and lysosomal degradation. May regulate IL6 signaling, decreasing cis signaling, possibly by interfering with IL6-binding to membrane-bound IL6R, while up-regulating trans signaling via soluble IL6R.

Subunit / interactions. After maturation cleavage, interacts (via N-terminus) with its own propeptide; this interaction prevents interaction with other ligands, including CRLF1, GDNF, GFRA1, IL6 and IL6R. Interacts (via N-terminal ectodomain) with APP, forming a 1:1 stoichiometric complex, including with isoforms APP695, APP751 and APP770; this interaction retains APP in the trans-Golgi network and reduces processing into soluble APP-alpha and amyloid-beta peptides. Also interacts with APP C-terminal fragment C99 and with Abeta40. Interacts with beta-secretase BACE1/BACE; this interaction may affect BACE1-binding to APP and hence reduce BACE1-dependent APP cleavage. Interacts with LRPAP1/RAP. Interacts (via C-terminal cytosolic domain) with GGA1 and GGA2 (via N-terminal VHS domain). Interacts with PACS1. May interact (via the N-terminal ectodomain) with the morphogenetic neuropeptide, also called head activator or HA; this interaction is impaired in the presence of propeptide. Interacts with neurotensin/NTS. Interacts (via the N-terminal ectodomain) with PDGFB homodimer. Interacts (via N-terminal ectodomain) with the uPA receptor PLAUR; this interaction decreases PLAUR internalization. Interacts (via N-terminal ectodomain) with uPA/PLAU and PAI1/SERPINE1, either individually or in complex with each other, leading to endocytosis; this interaction is abolished in the presence of LRPAP1. Also interacts with the ternary complex composed of PLAUR-PLAU-PAI1. Also interacts with tPA/PLAT either alone or in complex with SERPINE1. Interacts (via C-terminus) with AP-1 and AP-2 complexes. Interacts with BMPR1A and BMPR1B. Interacts with lipoprotein lipase LPL; this interaction is optimal in slightly acidic conditions. Interacts (via N-terminal ectodomain) with GDNF (via propeptide) and GDNF receptor alpha-1/GFRA1, either individually or in complex with each other. The interaction with GDNF occurs mostly intracellularly. Also interacts with other GDNF receptor alpha family members, including GFRA2, GFRA3 and GFRA4. Interacts with the insulin receptor INSR; this interaction strongly increases the surface exposure of INSR. Interacts (via cytosolic C-terminus) with STK39/SPAK. Interacts (via N-terminal ectodomain) with the heterodimeric complex CRLF1-CLC; within this complex, the interaction is mediated predominantly by the CRLF1 moiety. Interacts with CNTFR, as well as with the tripartite signaling complex formed by CRLF1, CLC and CNTFR. Interacts (via N-terminal ectodomain) with IL6; this interaction leads to IL6 internalization and lysosomal degradation. Binding of SOLRL1 secreted N-terminal ectodomain to IL6 may increase IL6 trans signaling. Interacts with secreted IL6R; this interaction leads to IL6R internalization. Also interacts with transmembrane IL6R; this interaction does not affect IL6R subcellular location. Interacts with APOE. Interacts with apolipoprotein E-rich beta-VLDL. Interacts with APOA5; this interaction leads to APOA5 internalization and is abolished by heparin. Interaction with APOA5 results in enhanced binding to chylomicrons. Interacts with ROCK2. Interacts (via cytosolic C-terminus) with PPP3CB/calcineurin A beta. Interacts with NTRK2/TRKB; this interaction facilitates NTRK2 trafficking between synaptic plasma membranes, postsynaptic densities and cell soma, hence positively regulates BDNF signaling. Interacts (via cytosolic C-terminus) with HSPA12A in an ADP-dependent manner; this interaction affects SORL1 internalization and subcellular localization. Interacts (via N-terminal ectodomain) with ERBB2/HER2.

Subcellular location. Golgi apparatus membrane. Golgi apparatus. trans-Golgi network membrane. Endosome membrane. Early endosome membrane. Recycling endosome membrane. Endoplasmic reticulum membrane. Endosome. Multivesicular body membrane. Cell membrane. Cytoplasmic vesicle. Secretory vesicle membrane. Secreted.

Tissue specificity. Highly expressed in brain (at protein level). Most abundant in the cerebellum, cerebral cortex and occipital pole; low levels in the putamen and thalamus. Expression is significantly reduced in the frontal cortex of patients suffering from Alzheimer disease. Also expressed in spinal cord, spleen, testis, prostate, ovary, thyroid and lymph nodes.

Post-translational modifications. Within the Golgi apparatus, the propeptide may be cleaved off by FURIN or a furin-like protease. After cleavage, the propeptide interacts with the mature protein N-terminus, preventing the association with other ligands. At the cell surface, partially subjected to proteolytic shedding that releases the ectodomain in the extracellular milieu. The shedding may be catalyzed by ADAM17/TACE. Following shedding, PSEN1/presenilin-1 cleaves the remaining transmembrane fragment and catalyzes the release of a C-terminal fragment in the cytosol and of a soluble N-terminal beta fragment in the extracellular milieu. The C-terminal cytosolic fragment localizes to the nucleus. Phosphorylation at Ser-2206 facilitates the interaction with GGA1.

Disease relevance. Alzheimer disease (AD) [MIM:104300] Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. The gene represented in this entry may be involved in disease pathogenesis.

Induction. Up-regulated by morphogenetic neuropeptide, also called head activator or HA. Up-regulated under hypoxic conditions in hematopoietic stem and progenitor cells, a physiological condition encountered by these cells in the endosteum. This up-regulation may be mediated by HIF1A-induced transcription.

Miscellaneous. There may be a positive correlation of body mass index with levels of SORL1 transcript and SORLA protein in visceral adipose tissue.

Similarity. Belongs to the VPS10-related sortilin family. SORL1 subfamily.

RefSeq proteins (1): NP_003096* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000033	LDLR_classB_rpt	Repeat
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR003961	FN3_dom	Domain
IPR006581	VPS10	Domain
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR023415	LDLR_class-A_CS	Conserved_site
IPR031777	Sortilin_C	Domain
IPR031778	Sortilin_N	Domain
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR050310	VPS10-sortilin	Family
IPR057841	FN3_SORL1	Domain

Pfam: PF00041, PF00057, PF00058, PF15901, PF15902, PF25814

UniProt features (228 total): strand 72, disulfide bond 39, glycosylation site 27, domain 19, mutagenesis site 14, helix 14, sequence variant 11, repeat 10, turn 5, region of interest 5, short sequence motif 4, topological domain 2, modified residue 2, signal peptide 1, propeptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
3G2S	X-RAY DIFFRACTION	1.7
3G2T	X-RAY DIFFRACTION	2
3WSX	X-RAY DIFFRACTION	2.35
3WSY	X-RAY DIFFRACTION	3.11
3WSZ	X-RAY DIFFRACTION	3.2
7VT0	ELECTRON MICROSCOPY	3.4
2DM4	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92673-F1	73.77	0.15

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 114, 2206

Disulfide bonds (39): 1368–1381, 1376–1394, 1388–1403, 1419–1431, 1426–1444, 1438–1453, 1471–1484, 1478–1497, 1491–1506, 1514–1527, 1521–1540, 1534–1549, 467–473, 625–660, 643–675, 677–736, 684–699, 716–752, 1078–1090, 1085–1103 …

Glycosylation sites (27): 99, 158, 368, 430, 616, 674, 818, 871, 1035, 1068, 1164, 1191, 1246, 1367, 1458, 1608, 1706, 1733, 1809, 1854 …

Mutagenesis-validated functional residues (14):

Position	Phenotype
78–81	loss of propeptide cleavage.
2163–2164	affects the nuclear location of the c-terminal fragment generated by psen1.
2172–2177	no effect on endocytosis.
2190–2214	strong reduction in golgi apparatus - endosome sorting. loss of interaction with ap-1 complex.
2190–2198	loss of interaction with gga1 and pacs1. no effect on interaction with app. affects subcellular location, increasing loc
2190–2191	no effect on the interaction with hspa12a.
2194–2198	strong decrease in interaction with hspa12a.
2201–2202	no effect on endocytosis. decreased golgi apparatus - endosome sorting.
2203–2204	no effect on the interaction with hspa12a.
2205–2206	no effect on the interaction with hspa12a.
2207–2208	strong decrease in interaction with hspa12a.
2208–2211	loss of interaction with gga1 and pacs1. no effect on interaction with app. affects subcellular location, by causing inc
2209–2210	no effect on the interaction with hspa12a.
2211–2214	no effect on endocytosis. affects lpl sorting to endosomes.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-977225	Amyloid fiber formation
R-HSA-392499	Metabolism of proteins

MSigDB gene sets: 679 (showing top): RNGTGGGC_UNKNOWN, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_LYSOSOMAL_TRANSPORT, MCLACHLAN_DENTAL_CARIES_UP, MODULE_169, GOBP_REGULATION_OF_TRIGLYCERIDE_METABOLIC_PROCESS, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_RESPONSE_TO_DIETARY_EXCESS, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT

GO Biological Process (33): diet induced thermogenesis (GO:0002024), protein targeting (GO:0006605), protein targeting to lysosome (GO:0006622), post-Golgi vesicle-mediated transport (GO:0006892), receptor-mediated endocytosis (GO:0006898), neuropeptide signaling pathway (GO:0007218), negative regulation of triglyceride catabolic process (GO:0010897), regulation of smooth muscle cell migration (GO:0014910), cell migration (GO:0016477), negative regulation of BMP signaling pathway (GO:0030514), negative regulation of protein-containing complex assembly (GO:0031333), protein localization to Golgi apparatus (GO:0034067), insulin receptor recycling (GO:0038020), retrograde transport, endosome to Golgi (GO:0042147), protein retention in Golgi apparatus (GO:0045053), positive regulation of protein catabolic process (GO:0045732), positive regulation of insulin receptor signaling pathway (GO:0046628), negative regulation of neurogenesis (GO:0050768), positive regulation of protein exit from endoplasmic reticulum (GO:0070863), endosome to plasma membrane protein transport (GO:0099638), positive regulation of glial cell-derived neurotrophic factor production (GO:1900168), negative regulation of amyloid-beta formation (GO:1902430), positive regulation of ER to Golgi vesicle-mediated transport (GO:1902953), obsolete positive regulation of early endosome to recycling endosome transport (GO:1902955), positive regulation of protein localization to early endosome (GO:1902966), negative regulation of amyloid precursor protein catabolic process (GO:1902992), negative regulation of neurofibrillary tangle assembly (GO:1902997), positive regulation of adipose tissue development (GO:1904179), adaptive thermogenesis (GO:1990845), positive regulation of endocytic recycling (GO:2001137), endocytosis (GO:0006897), vesicle-mediated transport (GO:0016192), amyloid-beta formation (GO:0034205)

GO Molecular Function (9): amyloid-beta binding (GO:0001540), transmembrane signaling receptor activity (GO:0004888), low-density lipoprotein particle receptor activity (GO:0005041), aspartic-type endopeptidase inhibitor activity (GO:0019828), low-density lipoprotein particle binding (GO:0030169), small GTPase binding (GO:0031267), neuropeptide binding (GO:0042923), protein transporter activity (GO:0140318), protein binding (GO:0005515)

GO Cellular Component (27): Golgi membrane (GO:0000139), obsolete extracellular space (GO:0005615), nuclear envelope lumen (GO:0005641), endosome (GO:0005768), early endosome (GO:0005769), multivesicular body (GO:0005771), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), endosome membrane (GO:0010008), membrane (GO:0016020), transport vesicle membrane (GO:0030658), early endosome membrane (GO:0031901), Golgi cisterna (GO:0031985), multivesicular body membrane (GO:0032585), neuronal cell body (GO:0043025), recycling endosome (GO:0055037), recycling endosome membrane (GO:0055038), extracellular exosome (GO:0070062), perinucleolar compartment (GO:0097356), extracellular region (GO:0005576), endomembrane system (GO:0012505), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
bounding membrane of organelle	3
endomembrane system	3
cytoplasm	3
cellular anatomical structure	3
peptide binding	2
endosome	2
intracellular membrane-bounded organelle	2
Golgi apparatus subcompartment	2
cytoplasmic vesicle membrane	2
response to dietary excess	1
adaptive thermogenesis	1
establishment of protein localization	1
protein targeting to vacuole	1
lysosomal transport	1
protein localization to lysosome	1
Golgi vesicle transport	1
endocytosis	1
G protein-coupled receptor signaling pathway	1
regulation of triglyceride catabolic process	1
triglyceride catabolic process	1
negative regulation of lipid catabolic process	1
negative regulation of triglyceride metabolic process	1
smooth muscle cell migration	1
regulation of cell migration	1
cell motility	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
regulation of protein-containing complex assembly	1
negative regulation of cellular component organization	1
protein-containing complex assembly	1
protein localization to organelle	1
receptor recycling	1
positive regulation of insulin receptor signaling pathway	1
intercellular transport	1
endosomal transport	1
cytosolic transport	1
maintenance of protein location in cell	1
protein localization to Golgi apparatus	1

Protein interactions and networks

STRING

2036 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SORL1	APOE	P02649	995
SORL1	APP	P05067	994
SORL1	VPS26A	O75436	931
SORL1	CLU	P10909	861
SORL1	NTS	P30990	852
SORL1	ABCA7	Q8IZY2	834
SORL1	PICALM	Q13492	823
SORL1	MDK	P21741	818
SORL1	CD33	P20138	808
SORL1	BLID	Q8IZY5	807
SORL1	BIN1	O00499	798
SORL1	VPS35	Q96QK1	797
SORL1	SNX27	Q96L92	785
SORL1	PSEN1	P49768	779
SORL1	PSEN2	P49810	779

IntAct

291 interactions, top by confidence:

A	B	Type	Score
DLD	PDHX	psi-mi:“MI:0914”(association)	0.880
SORL1	SORL1	psi-mi:“MI:0407”(direct interaction)	0.810
LRPAP1	SORL1	psi-mi:“MI:0407”(direct interaction)	0.800
SORL1	GGA2	psi-mi:“MI:0915”(physical association)	0.770
GGA2	SORL1	psi-mi:“MI:0915”(physical association)	0.770
SORL1	GGA1	psi-mi:“MI:0915”(physical association)	0.740
SORL1	APP	psi-mi:“MI:0407”(direct interaction)	0.730
SORL1	APP	psi-mi:“MI:0915”(physical association)	0.730
SORL1	APP	psi-mi:“MI:0403”(colocalization)	0.730
SORL1	APP	psi-mi:“MI:2364”(proximity)	0.730
APP	SORL1	psi-mi:“MI:2364”(proximity)	0.730
SORL1	APP	psi-mi:“MI:0915”(physical association)	0.690
SORL1	APP	psi-mi:“MI:0403”(colocalization)	0.690
APP	SORL1	psi-mi:“MI:0915”(physical association)	0.690
CNTFR	SORL1	psi-mi:“MI:0403”(colocalization)	0.670
CNTFR	SORL1	psi-mi:“MI:0407”(direct interaction)	0.670
CNTFR	SORL1	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (197): APP (Affinity Capture-Western), GGA1 (Affinity Capture-Western), SORL1 (Affinity Capture-Western), SORL1 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), SORL1 (Affinity Capture-MS)

ESM2 similar proteins: A0M8S8, A1X150, A1Z6H7, G0SB44, G5ED46, H2KYE0, H2KZ60, O08775, O18016, O44386, O45657, O73798, O88307, O94385, P0DSP1, P16056, P30639, P35918, P46555, P98094, Q00685, Q00PJ8, Q02763, Q02858, Q03600, Q06807, Q07E01, Q07E24, Q07E37, Q09417, Q18264, Q24247, Q2IBC0, Q2QLC0, Q2QLG5, Q5MD89, Q60PR7, Q626H5, Q75ZY9, Q769I5

Diamond homologs: A2AR95, A2ARV4, A4IHY6, C0HL13, E9Q6D8, G3V928, O75074, O75197, O75581, O88204, O88307, O88572, P0DSP1, P13671, P35953, P56677, P61134, P61135, P86091, P98153, P98154, P98155, P98156, P98157, P98158, P98160, P98163, P98164, P98165, P98166, P98167, Q04833, Q06561, Q07954, Q0IIH7, Q14114, Q28832, Q29RU4, Q5HZW5, Q5R662

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
APOE	up-regulates	SORL1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

912 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	7
Uncertain significance	509
Likely benign	224
Benign	82

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1405874	NM_003105.6(SORL1):c.2187del (p.Lys730fs)	Pathogenic
1439318	NM_003105.6(SORL1):c.862del (p.Glu288fs)	Pathogenic
1451658	NM_003105.6(SORL1):c.3712A>T (p.Lys1238Ter)	Pathogenic
1452991	NM_003105.6(SORL1):c.919del (p.Met307fs)	Pathogenic
2137276	NM_003105.6(SORL1):c.2230C>T (p.Arg744Ter)	Pathogenic
2169564	NM_003105.6(SORL1):c.2596C>T (p.Arg866Ter)	Pathogenic
2424626	NC_000011.9:g.(?121323041)(121500272_?)del	Pathogenic
2702184	NM_003105.6(SORL1):c.1825_1828del (p.Ser609fs)	Pathogenic
2735780	NM_003105.6(SORL1):c.802C>T (p.Arg268Ter)	Pathogenic
2811654	NM_003105.6(SORL1):c.3193C>T (p.Gln1065Ter)	Pathogenic
2855738	NM_003105.6(SORL1):c.4362_4365CTTG[1] (p.Leu1456fs)	Pathogenic
2865978	NM_003105.6(SORL1):c.4293del (p.Cys1431fs)	Pathogenic
3238954	NM_003105.6(SORL1):c.1211+1G>A	Pathogenic
3694306	NM_003105.6(SORL1):c.1969dup (p.His657fs)	Pathogenic
3724199	NM_003105.6(SORL1):c.1349G>A (p.Trp450Ter)	Pathogenic
4715589	NM_003105.6(SORL1):c.2639dup (p.Leu881fs)	Pathogenic
4751050	NM_003105.6(SORL1):c.835C>T (p.Arg279Ter)	Pathogenic
4770553	NM_003105.6(SORL1):c.5125G>T (p.Glu1709Ter)	Pathogenic
2775834	NM_003105.6(SORL1):c.2051+1G>A	Likely pathogenic
3664354	NM_003105.6(SORL1):c.2911-2A>C	Likely pathogenic
3700144	NM_003105.6(SORL1):c.6172-1G>A	Likely pathogenic
4713652	NM_003105.6(SORL1):c.2903_2910+174del	Likely pathogenic
4732686	NM_003105.6(SORL1):c.2907_2910+15del	Likely pathogenic
4732725	NM_003105.6(SORL1):c.5808_5889+2delinsG	Likely pathogenic
982188	NM_003105.6(SORL1):c.2878C>G (p.Leu960Val)	Likely pathogenic

SpliceAI

7672 predictions. Top by Δscore:

Variant	Effect	Δscore
11:121452615:AGG:A	donor_loss	1.0000
11:121452617:G:A	donor_loss	1.0000
11:121452618:T:A	donor_loss	1.0000
11:121470119:GTGAT:G	donor_gain	1.0000
11:121470121:GAT:G	donor_gain	1.0000
11:121470123:TG:T	donor_loss	1.0000
11:121470124:G:GG	donor_gain	1.0000
11:121470124:GT:G	donor_loss	1.0000
11:121470125:T:G	donor_loss	1.0000
11:121478108:T:A	acceptor_gain	1.0000
11:121478111:A:AG	acceptor_gain	1.0000
11:121478114:CCA:C	acceptor_loss	1.0000
11:121478115:CAGGT:C	acceptor_loss	1.0000
11:121478116:A:AG	acceptor_gain	1.0000
11:121478116:AGGT:A	acceptor_gain	1.0000
11:121478117:G:GG	acceptor_gain	1.0000
11:121478117:GGT:G	acceptor_gain	1.0000
11:121478117:GGTG:G	acceptor_gain	1.0000
11:121478117:GGTGT:G	acceptor_gain	1.0000
11:121478239:AGCGG:A	donor_gain	1.0000
11:121478240:GCGG:G	donor_gain	1.0000
11:121478240:GCGGG:G	donor_gain	1.0000
11:121478242:GG:G	donor_gain	1.0000
11:121478243:GG:G	donor_gain	1.0000
11:121478244:G:GA	donor_loss	1.0000
11:121478244:G:GG	donor_gain	1.0000
11:121478245:T:A	donor_loss	1.0000
11:121478249:G:GT	donor_gain	1.0000
11:121488029:CA:C	acceptor_loss	1.0000
11:121488030:A:AG	acceptor_gain	1.0000

AlphaMissense

14744 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:121619882:T:A	W1952R	1.000
11:121619882:T:C	W1952R	1.000
11:121490052:T:C	S234P	0.999
11:121490073:T:A	W241R	0.999
11:121490073:T:C	W241R	0.999
11:121522981:T:A	W530R	0.999
11:121522981:T:C	W530R	0.999
11:121543690:T:A	W610R	0.999
11:121543690:T:C	W610R	0.999
11:121555188:G:C	R814P	0.999
11:121570240:T:A	C1103S	0.999
11:121570240:T:C	C1103R	0.999
11:121570241:G:A	C1103Y	0.999
11:121570241:G:C	C1103S	0.999
11:121570242:T:G	C1103W	0.999
11:121574333:T:A	C1144S	0.999
11:121574333:T:C	C1144R	0.999
11:121574334:G:A	C1144Y	0.999
11:121574334:G:C	C1144S	0.999
11:121574335:T:G	C1144W	0.999
11:121577367:T:A	C1183S	0.999
11:121577367:T:C	C1183R	0.999
11:121577368:G:A	C1183Y	0.999
11:121577368:G:C	C1183S	0.999
11:121577369:C:G	C1183W	0.999
11:121583525:G:C	W1216C	0.999
11:121583525:G:T	W1216C	0.999
11:121625203:T:A	V2097D	0.999
11:121470046:T:A	W109R	0.998
11:121470046:T:C	W109R	0.998

dbSNP variants (sampled 300 via entrez): RS1000025729 (11:121485609 G>A), RS1000035367 (11:121501461 A>G), RS1000048256 (11:121617892 C>T), RS1000049138 (11:121543375 T>G), RS1000080868 (11:121550338 C>G,T), RS1000081346 (11:121472976 A>AG,AT), RS1000086942 (11:121490195 C>A,T), RS1000093497 (11:121631904 C>G,T), RS1000103657 (11:121575097 G>C), RS1000151359 (11:121590237 G>A), RS1000169807 (11:121523331 A>C,G), RS1000180968 (11:121608277 A>G), RS1000185424 (11:121607863 A>C,G), RS1000189931 (11:121566442 T>C), RS1000194719 (11:121550427 G>A)

Disease associations

OMIM: gene MIM:602005 | disease phenotypes: MIM:608907

GenCC curated gene-disease

Disease	Classification	Inheritance
early-onset autosomal dominant Alzheimer disease	Supportive	Autosomal dominant

Mondo (3): Alzheimer disease 9 (MONDO:0012153), complex hereditary spastic paraplegia (MONDO:0015150), early-onset autosomal dominant Alzheimer disease (MONDO:0015140)

Orphanet (2): Complex hereditary spastic paraplegia (Orphanet:102013), Moyamoya angiopathy (Orphanet:477768)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000504	Abnormality of vision
HP:0000657	Oculomotor apraxia
HP:0000713	Agitation
HP:0000726	Dementia
HP:0000734	Disinhibition
HP:0000738	Hallucinations
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001276	Hypertonia
HP:0001289	Confusion
HP:0001300	Parkinsonism
HP:0001336	Myoclonus
HP:0002120	Cerebral cortical atrophy
HP:0002185	Neurofibrillary tangles
HP:0002186	Apraxia
HP:0002354	Memory impairment
HP:0002381	Aphasia
HP:0002463	Language impairment
HP:0003791	Deposits immunoreactive to beta-amyloid protein
HP:0010525	Finger agnosia
HP:0010526	Dysgraphia
HP:0011446	Abnormality of mental function
HP:0012433	Abnormal social behavior
HP:0012759	Neurodevelopmental abnormality
HP:0030219	Semantic dementia

GWAS associations

33 associations (top):

Study	Trait	p-value
GCST000789_4	Cardiovascular risk factors (age interaction)	3.000000e-06
GCST001947_1	Alzheimer’s disease (late onset)	2.000000e-09
GCST002245_4	Alzheimer’s disease (late onset)	1.000000e-14
GCST002751_5	Spontaneous preterm birth (preterm birth)	3.000000e-06
GCST002817_17	Alzheimer’s disease in APOE e4- carriers	9.000000e-06
GCST002864_1	Mood disorder in prion disease	4.000000e-06
GCST002936_6	Cadmium levels	6.000000e-06
GCST006061_199	Atrial fibrillation	5.000000e-11
GCST006414_6	Atrial fibrillation	5.000000e-09
GCST006976_42	Macular thickness	8.000000e-16
GCST006979_229	Heel bone mineral density	9.000000e-13
GCST007319_24	Alzheimer’s disease (late onset)	6.000000e-11
GCST007320_101	Alzheimer’s disease or family history of Alzheimer’s disease	1.000000e-11
GCST007321_9	Family history of Alzheimer’s disease	3.000000e-06
GCST007327_102	Smoking status (ever vs never smokers)	3.000000e-10
GCST007327_69	Smoking status (ever vs never smokers)	4.000000e-08
GCST007328_21	Alcohol consumption (drinks per week)	5.000000e-12
GCST007466_13	Word reading	6.000000e-06
GCST007478_16	Non-word reading	2.000000e-06
GCST008058_148	Estimated glomerular filtration rate	1.000000e-14
GCST008059_46	Estimated glomerular filtration rate	8.000000e-14
GCST008062_92	Blood urea nitrogen levels	5.000000e-06
GCST008522_48	Bitter alcoholic beverage consumption	1.000000e-08
GCST008747_170	Estimated glomerular filtration rate	1.000000e-08
GCST008747_40	Estimated glomerular filtration rate	3.000000e-06
GCST008757_47	Alcohol consumption	6.000000e-11
GCST008811_4	Alcohol consumption (drinks per week)	7.000000e-09
GCST009021_1	Alzheimer’s disease	1.000000e-10
GCST009797_7	Alcohol consumption (heavy vs. light/non-drinkers)	6.000000e-06
GCST010396_106	Gut microbiota (bacterial taxa, hurdle binary method)	5.000000e-07

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0008007	age at assessment
EFO:0006917	spontaneous preterm birth
EFO:0006921	birth measurement
EFO:0009270	heel bone mineral density
EFO:0009268	family history of Alzheimer’s disease
EFO:0004318	smoking behavior
EFO:0005300	word reading
EFO:0005299	non-word reading
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0007874	gut microbiome measurement
EFO:0009458	alcohol use disorder measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563834	Alzheimer Disease 9 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

90 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects binding, increases reaction, decreases expression, increases expression	6
Benzo(a)pyrene	decreases methylation, increases expression, affects methylation, decreases expression	5
Cyclosporine	affects cotreatment, decreases expression, increases expression	5
Acetaminophen	affects expression, decreases expression, affects cotreatment	4
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	affects methylation, decreases expression, increases expression	3
Air Pollutants	decreases expression, affects expression, increases abundance	3
Tobacco Smoke Pollution	decreases expression, decreases methylation, increases expression	3
Tretinoin	increases expression	3
Valproic Acid	affects expression, decreases expression, increases expression	3
methylmercuric chloride	decreases expression	2
bisphenol A	increases methylation, decreases expression, affects cotreatment	2
cobaltous chloride	decreases expression, increases expression, increases secretion	2
Arsenic	affects expression, affects methylation	2
Cisplatin	decreases expression	2
Doxorubicin	affects response to substance, decreases expression	2
Estradiol	increases expression, affects cotreatment, decreases expression	2
Oxygen	increases reaction, increases expression, increases secretion, affects binding	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
GSK-J4	increases expression	1
chloroacetaldehyde	affects expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
quercitrin	decreases expression	1
hydroxyhydroquinone	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1

Cellosaurus cell lines

16 cell lines: 14 induced pluripotent stem cell, 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C0YV	UMi038-A	Induced pluripotent stem cell	Female
CVCL_C0YW	UMi039-A	Induced pluripotent stem cell	Female
CVCL_C0YX	UMi038-B	Induced pluripotent stem cell	Female
CVCL_C0YY	UMi039-B	Induced pluripotent stem cell	Female
CVCL_C0YZ	UMi038-A-1	Induced pluripotent stem cell	Female
CVCL_C0Z0	UMi039-A-1	Induced pluripotent stem cell	Female
CVCL_E2KL	HAP1 SORL1 (-) 1	Cancer cell line	Male
CVCL_E2KM	HAP1 SORL1 (-) 2	Cancer cell line	Male
CVCL_E7MG	KOLF2.1J SORL1 G1681D SNV/WT	Induced pluripotent stem cell	Male
CVCL_E7MI	KOLF2.1J SORL1 T947M SNV/SNV	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05637801	Not specified	ACTIVE_NOT_RECRUITING	A Pivotal Study of Sensory Stimulation in Alzheimer’s Disease (HOPE Study)