No analysis on chromosome 23

[Avni Kaur]

Dear Fuma Team,

I realised FUMA has a problem with picking up my top hits /SNPs on chr 23. When I look at the published data already there seems to be no results on chr 23 for all the public datasets....

I thought initially it was something to do within my genetic file  - I've just taken a look, which shows the top SNP on chromosome 23 is present in the reference panel albeit in different RSID formats however SNPs will be matched by chr and position, if not matched by rsid. So I don't think there is an issue with my input genetic file. 

I would love for someone to confirm if this is the case as I would love to proceed with the analysis. 

Thanks

Avni

[Marijn Schipper]

Hi Avni,

Would you mind sharing your input file with me so I can try and troubleshoot your FUMA analysis?

Cheers,

Marijn

Op donderdag 19 mei 2022 om 17:35:22 UTC+2 schreef Avni Kaur:

[Avni Kaur]

Hi Martin,

Thanks for your response. If you share your email to me, I can send you the tail end of my file with the last hundred lines (all chr 23).

But I have pasted a couple lines below for now, all chr23, from my input genetic file. 

CHROM    POS    ID    REF    ALT    A1    TEST    OBS_CT    BETA    SE    T_STAT    P

X    154839087    rs522805:154839087:T:C    T    C    T    ADD    1585    0.0253515    0.016764    1.51226    0.13067
X    154842666    rs89278:154842666:C:T    C    T    C    ADD    1585    0.0270866    0.0170188    1.59157    0.111683
X    154844287    rs479901:154844287:A:T    A    T    A    ADD    1585    0.0253612    0.016766    1.51266    0.130568
X    154844660    rs476928:154844660:C:G    C    G    C    ADD    1585    0.0253101    0.0167549    1.5106    0.131091
X    154845104    rs561928:154845104:G:T    G    T    G    ADD    1585    0.0253608    0.0167659    1.51264    0.130573
X    154845739    rs556344:154845739:T:C    T    C    T    ADD    1585    0.0253604    0.0167659    1.51262    0.130578
X    154845770    rs500911:154845770:T:C    T    C    C    ADD    1585    -0.0082093    0.0234375    -0.350264    0.726188
X    154845791    rs11396863:154845791:C:CT    C    CT    C    ADD    1585    0.0249952    0.016769    1.49056    0.136279
X    154846104    rs498000:154846104:G:T    G    T    G    ADD    1585    0.0253101    0.0167549    1.5106    0.131091
X    154846835    rs580468:154846835:A:G    A    G    A    ADD    1585    0.0131436    0.0159615    0.823461    0.410371
X    154847489    rs574386:154847489:C:T    C    T    C    ADD    1585    0.0253087    0.0167554    1.51048    0.131123
X    154848759    rs146884178:154848759:T:TCTTAGAGCC    T    TCTTAGAGCC    T    ADD    1585    0.0255713    0.0167886    1.52313    0.127927
X    154849030    rs1834433:154849030:G:T    G    T    G    ADD    1585    0.0252854    0.0167644    1.50828    0.131686
X    154850125    rs672434:154850125:T:A    T    A    T    ADD    1585    0.0253631    0.016765    1.51286    0.130518
X    154850801    rs569049:154850801:T:C    T    C    T    ADD    1585    0.0253608    0.0167659    1.51264    0.130573
X    154851523    rs561841:154851523:G:A    G    A    G    ADD    1585    0.025315    0.0167564    1.51076    0.13105
X    154854178    X:154854178:C:CATCT    C    CATCT    CATCT    ADD    1585    0.0252869    0.0417899    0.605097    0.545202
X    154854338    rs140195596:154854338:A:G    A    G    G    ADD    1585    0.0536526    0.0400017    1.34126    0.180031
X    154854781    rs2162139:154854781:T:A    T    A    A    ADD    1585    0.0297303    0.0195141    1.52353    0.127828
X    154855371    rs56052902:154855371:A:G    A    G    G    ADD    1585    0.0128433    0.0454018    0.28288    0.777306
X    154855606    rs75097820:154855606:T:TTA    T    TTA    T    ADD    1585    0.0253608    0.0167659    1.51264    0.130573
X    154856281    rs654274:154856281:A:G    A    G    A    ADD    1585    0.0253608    0.0167659    1.51264    0.130573
X    154856709    rs666267:154856709:C:G    C    G    C    ADD    1585    0.0253101    0.0167549    1.5106    0.131091
X    154856764    rs666344:154856764:A:C    A    C    A    ADD    1585    0.0253443    0.016763    1.51191    0.130757
X    154856774    rs573685:154856774:T:A    T    A    T    ADD    1585    0.0253443    0.016763    1.51191    0.130757
X    154857484    rs5940546:154857484:C:G    C    G    G    ADD    1585    0.0132811    0.0501361    0.264901    0.791121
X    154858649    rs514136:154858649:C:T    C    T    C    ADD    1585    0.025408    0.0167695    1.51513    0.129941
X    154858725    rs513234:154858725:T:C    T    C    T    ADD    1585    0.0257171    0.0168153    1.52939    0.126369
X    154859910    rs144293808:154859910:A:C    A    C    C    ADD    1585    0.011834    0.0457655    0.258578    0.795995
X    154860283    rs622211:154860283:A:G    A    G    A    ADD    1585    0.025408    0.0167695    1.51513    0.129941
X    154865855    rs487307:154865855:A:G    A    G    A    ADD    1585    0.0251115    0.0167973    1.49497    0.135124
X    154865915    rs601290:154865915:G:A    G    A    G    ADD    1585    0.0253569    0.0167585    1.51308    0.130461
X    154870197    rs473772:154870197:T:C    T    C    T    ADD    1585    0.025408    0.0167695    1.51513    0.129941
X    154871743    rs528286:154871743:C:T    C    T    C    ADD    1585    0.0255653    0.0167857    1.52304    0.12795
X    154872707    rs612412:154872707:G:A    G    A    G    ADD    1585    0.025408    0.0167695    1.51513    0.129941
X    154873044    rs613783:154873044:C:A    C    A    C    ADD    1585    0.0131814    0.0159645    0.825665    0.40912
X    154874837    rs642362:154874837:A:G    A    G    A    ADD    1585    0.0254083    0.0167696    1.51514    0.129939
X    154875192    rs372034665:154875192:GTACTC:G    GTACTC    G    GTACTC    ADD    1585    0.0256109    0.0168108    1.52348    0.127841
X    154879115    rs150712976:154879115:A:G    A    G    A    ADD    1585    0.0254753    0.0167772    1.51845    0.129103
X    154880669    rs491661:154880669:T:A    T    A    T    ADD    1585    0.0253624    0.016759    1.51336    0.130389
X    154880917    rs494282:154880917:C:T    C    T    C    ADD    1585    0.0253624    0.016759    1.51336    0.130389
X    154881521    rs520792:154881521:G:A    G    A    G    ADD    1585    0.0132431    0.0159639    0.829569    0.406909
X    154885405    rs563690:154885405:G:A    G    A    G    ADD    1585    0.02543    0.0167707    1.51633    0.129636
X    154885878    rs608695:154885878:A:G    A    G    A    ADD    1585    0.02551    0.0167841    1.51989    0.12874
X    154886333    rs610828:154886333:A:G    A    G    A    ADD    1585    0.0254755    0.0167771    1.51846    0.129099
X    154887308    rs512918:154887308:G:A    G    A    G    ADD    1585    0.0132323    0.0159722    0.82846    0.407536
X    154887583    rs636742:154887583:C:T    C    T    C    ADD    1585    0.0254218    0.0167666    1.51622    0.129666
X    154887924    rs638156:154887924:T:A    T    A    T    ADD    1585    0.0254588    0.0167742    1.51774    0.129282
X    154888722    rs547437:154888722:G:A    G    A    G    ADD    1585    0.025614    0.0167905    1.52551    0.127334
X    154889423    rs671588:154889423:C:T    C    T    C    ADD    1585    0.0255079    0.0167848    1.51971    0.128786

Thanks

Avni

[Mauro Tutino]

Hi,

I am having the same issue. I have genome-wide hits in the Manhattan plot but they seem to disappear after that. Have you solved this?

Thank you

Mauro

[Marijn Schipper]

Hi Mauro, 
I am currently still working on the issue that Avni is facing.
Is your issue chr23 specific as well? 
If not I would recommend checking whether your missing hits are present in your selected reference panel (https://fuma.ctglab.nl/tutorial#refpanel).

Cheers,
Marijn

Op dinsdag 24 mei 2022 om 15:43:40 UTC+2 schreef Mauro Tutino:

[Mauro Tutino]

Hi,

I think the problem was that I used 1000G EUR and it does not include chrX. When I use UKB it does work. Maybe this is something that should be flagged up when choosing the Ref panel? Also, if some TopHits are excluded because not in the reference panel, can this be reported in a file that can be downloaded from the "Download" tab? I think it is something important to know :)

Thank you for the awesome tool btw 

Mauro

[Marijn Schipper]

Hi Mauro,

Thank you for your response. We are still figuring out why some variants are removed particularly on chr23, The 1KG EUR does include chr 23.
Avni correctly found that chr 23 SNPs were dropped which are part of the reference panel, we are still figuring out why. 
I like your suggestion to more clearly state that lead SNPs were dropped if they are not part of the reference panel, and we'll take that into consideration for future FUMA updates.

Cheers,
Marijn 

Op vrijdag 27 mei 2022 om 12:02:02 UTC+2 schreef Mauro Tutino:

[Z S]

Yes, I can confirm this issue. In January, I run FUMA with my file, and then FUMA can work with chrX. But, recently I submitted the same file that I used in January, and then it does not add any annotations on ChrX. So, I think this issue remains. But, I am not sure how to fix it.

Thanks.

[Marijn Schipper]

Dear Avni, Mauro and Z S,

This issue should be resolved as of 30-8-2022.
If your analysis now includes chromosome X it would be of great help to me if you confirm that your problem has been resolved.
If the issue persists please let me know so I can continue to troubleshoot the problem that is causing your variants to be dropped.

Cheers,

Marijn

Op vrijdag 26 augustus 2022 om 09:13:00 UTC+2 schreef Z S:

[Z S]

Hi Marijn,

Thanks for your reply. I found the issue remains. When I submitted the GWAS summary statistics to FUMA (job ID: 201986), I found all SNPs on the sex chromosome (ChrX) had been removed. In the GWAS summary statistics, the sex chromosome has been labeled as "23", below
SNP CHR POS P
rs538470 23 154925895 0.052209845528399385
rs644138 23 154927581 0.00319363704232494
rs557132 23 154929412 0.05243934857786004
rs762503228 23 154929637 0.10711639408409107
rs775521832 23 154929952 0.079950603660104
rs781880 23 154930230 0.05786215174796438
rs781879 23 154930487 0.4821331943032956

I also change the label to chrX, as follows. But I found the issue remains.

SNP CHR POS P
rs538470 X 154925895 0.052209845528399385
rs644138 X 154927581 0.00319363704232494
rs557132 X 154929412 0.05243934857786004
rs762503228 X 154929637 0.10711639408409107

I run FUMA with the same file in January, at that time it indeed determined the lead SNPs on ChrX and added relevant annotations. But now, I submitted the same file that I used in January, it seems not to work with ChrX. In addition, I am sure there are lots of significant SNPs on ChrX.

Do you have any suggestions on this issue?

Best,

Cain

[Marijn Schipper]

Dear Cain,

I just ran your snippit of input with the p value of rs557132 lowered to your selected leadP value treshold of 2.5e-8:

SNP CHR POS P
rs538470 X 154925895 0.052209845528399385
rs644138 X 154927581 0.00319363704232494

rs557132 X 154929412 0.000000000005243934857786004
rs762503228 X 154929637 0.10711639408409107

After the bugfix of yesterday my FUMA output shows that indeed a risk loci is detected with  rs557132 as lead variant. 
Please doublecheck if there are variants below 2.5e-8 present on the X chromosome in your GWAS.
If this is the case, please check if these variants are present in the reference panel you selected: 1KG European, more info can be found here:
https://fuma.ctglab.nl/tutorial#refpanel

If the variants are below your selected p-value threshold and part of the reference panel you can send your input file with me at m.j.sc...@vu.nl so I can see why your variants are filtered out.

Cheers,

Marijn

Op dinsdag 30 augustus 2022 om 17:17:44 UTC+2 schreef Z S:

[Z S]

Hi Marijn,

Thanks for your reply. I found it works now, I guess the reason why it previously did not work with the same input file is that the FUMA server might be busy in computing at that time. So, just now FUMA was not that busy, and then it run smoothly as usual.

Anyway, thanks again.