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The alzforum url suggested that the SORL1 variants not be reported as causal of dementia without further confirmation. The variants that have been found are quite rare and it might be quite some time before everything is sorted out. SORL1 was first identified as an AD risk gene 10 years ago. It is only within the last few weeks that it has become clearer that it might be an AD autosomal dominant gene. Perhaps snpedia could play a helpful role here by providing the information about the rare SORL1 variants in Promethease reports without making strong claims of causality. Those who were interested in pursuing this further might be directed to the AD genetics researchers who would likely be very interested in speaking with those who have rare likely causal dementia variants.


These are the variants that were found in the latest study. Many of these only had a single patient with AD. When the rare variants were all collapsed into their genes, SORL1 was found to be significantly related to AD (Table 2 below).

I am not sure what the rs numbers are for the below variants. p.Arg744?

Table 3. SORL1 variants Genomic Position Variant Type Variant Class CADD score Protein modification ExAC Global Frequency Case/ Control Sex Ethnicity Braak Stage Age atOnset or LastVisit

11-1213675 77 snv SAV 26.6 NA 0 case F AA NA 77 11-1213676 54 snv SG 37 p.Arg279* 0 case F NHW 6 72 11-1214213 43 22 23 snv SG 39 p.Arg744* 0 case M NHW NA 65 11-1214213 43 2223 snv SG 39 p.Arg744* 0 case F NHW NA 67 11-1214260 01 indel FV NA p.Asp850fs 0 case F NHW NA 60 11-1214280 47 snv SG 41 p.Arg866* 0 case M NHW 6 65 11-1214302 63 indel FV NA p.Ile983fs 0 ctrl M AA NA 64 11-1214409 80 snv SDV 27.6 NA 4.95E-05 case F CH NA 80 11-1214569 30 snv SAV 26.8 NA 0 case M NHW NA 69 11-1214569 30 snv SAV 26.8 NA 0 case M NHW 6 62 11-1214617 88 indel FV NA p.Cys1431fs 0 case F NHW NA 61 11-1214664 82 2425 snv SDV 28 NA 0 case F NHW 3 90+ 11-1214664 822425snv SDV 28 NA 0 case F NHW NA 90+ 11-1214749 11 indel FV NA p.Thr1511fs 0 case M NHW NA 60 11-1214749 84 snv SG 35 p.Cys1534* 0 case F NHW NA 74 11-1214775 682425snv SG 46 p.Arg1655* 0 case M NHW NA 69 11-1214776 67 snv SDV 26.9 NA 0 case F AA NA 68 11-1214856 37 indel FV NA p.Asp1828fs 0 case M NHW NA 75 11-1214918 01 indel FV NA p.Lys1975fs 0 case M NHW 6 61 11-1215002 53 indel FV NA p.Met2211fs 0 case M NHW 6 62

(page 27 of 29 of https://www.biorxiv.org/content/early/2018/04/20/305631.full.pdf+html)

Supplemental Table 2. Genes in which LoF variants reach p <0.05 in Fisher's Exact Test between cases and controls

Gene Name Total Variant Total SNV Total Indel No. of Cases w/ Variant Case Freq No. of Cntrls w/ Variant Cntrl Freq Enriched Direction Fet P pLI LoF depletion FDR

SORL1 17 10 7 19 0.0027 1 7.56E-05 case 2.17E-08 <0.9 1.98E-07 GRID2IP 12 4 8 11 0.0016 2 1.51E-04 case 2.98E-04 <0.9 >=0.01 WDR76 10 3 7 10 0.0014 2 1.51E-04 case 7.39E-04 <0.9 >=0.01 GRN 12 6 6 11 0.0016 3 2.27E-04 case 9.56E-04 <0.9 7.86E-03


The highest magnitude I see is a 1.01, which is about as low as you could possibly have.
"not be reported as causal of dementia without further confirmation", I think we always make similar statements, and would be curious if you see anything different in SNPedia? --- cariaso 06:03, 15 June 2018 (UTC)

-- The dramatically important development is that SORL1 appears to be causal for Alzheimer's.

APP gene variants (such as rs63750973) that are autosomal dominant for Alzheimer's have a magnitude of 6-8 on snpedia. There are only 4 other genes that have been found that greatly increase or even cause AD. All other AD variants individually confer minimal risk. SORL1 variants would, thus, be highly relevant to report to Promethease users.

"ApoE4 and TREM2 boost a person’s odds of late-onset AD from three- to 12-fold, and the three autosomal-dominant genes APP, PS1, and PS2 bring on AD with near certainty. All other AD genes confer much smaller odds. Or so we thought. Growing evidence now suggests that a sixth gene, the endocytic receptor SORL1, deserves a place among this set. Several recent studies have identified pathogenic SORL1 variants that segregate with the disease in families. Now, researchers led by Richard Mayeux at Columbia University in New York report finding 17 rare loss-of-function SORL1 variants in a large whole-exome sequencing study. The variants occurred exclusively in people with cognitive impairment or AD, never in healthy controls. This strengthens the case that they cause disease...

There is no longer any doubt SORL1 is a major genetic determinant of Alzheimer's disease, probably by participating in a central pathophysiological pathway,...

rare, pathogenic SORL1 missense mutations confer about a 12-fold increased risk of AD, similar to ApoE4 homozygosity...

rare, damaging SORL1 mutations in 2 percent of AD cases" https://www.alzforum.org/news/research-news/gaining-notoriety-sorl1-claims-spot-among-top-alzheimers-genes

":"not be reported as causal of dementia without further confirmation", I think we always ... in SNPedia? ---"

I included the "not be reported" statement based on what I read in the alzforum article. Even with all the current evidence the AD researchers were still urging caution about how the risk from SORL1 rare variants should be conveyed to carriers. The recent study found only single instances of some of the super rare SORL1 variants, so it is entirely possible that others carry the same variants and will not develop dementia.

I think this is an extremely large opportunity for snpedia to help the research effort. All of the rare and likely causal variants in SORL1 could be added to the snpedia database and reported during a Promethease run. Users who were carriers for these variants could then be provided with contact information of those in the AD research community and connect with them if they chose to do so.J1 (talk)