mQTLs in ART

parents vs children




Julia Romanowska

2024-08-09

Photo by Sergei Gussev on Unsplash

OUTLINE

mQTLs

DNAm reprogramming

methods

some results

discussion

mQTL

SNP–CpG pair

  • cis-mQTLs and trans-mQTLs

  • indicating a functional connection between
    methylation status of that CpG and
    allele at that SNP

DNAm reprogramming

wave of demethylation followed by rapid re-methylation

  • paternal DNA is demethylated faster than maternal

  • at blastocyst stage, DNAm level is lowest (ca.20% of all CpGs)

  • freezing of eggs could influence de-methylation and differentiation

[src: Albert and Greenberg, Development (2023); Greenberg, Front.Cell Develop.Biol. (2021)]

Aim

to check for differences in existence of mQTLs between:

  • parents vs children

  • ART vs non-ART

methods

data

  • genetic data - MoBa

  • epigenetic data - START

Boxplot showing that number of samples available in each category is comparable: 819 non-ART mothers, 779 ART mothers, 808 non-ART fathers, 784 ART fathers, 911 non-ART children, and 847 ART children.

methods

tools

  • PLINK

  • (MatrixEQTL package)

  • snakemake

methods

  1. agnostic search for mQTLs in parents

  2. select the significant mQTLs

  3. check for association in children
    using two models:

  • DNAm \(\sim\) SNP \(+\) case_control_status
  • DNAm \(\sim\) SNP \(\times\) case_control_status

Results

mQTLs in parents

How many mQTL pairs?

for chromosome 20 only!

# tests # all mQTLs # signif mQTLs[*]
cis 107225852 107225852 6175
trans 3191581264 256233 9105

Where are the significant mQTL pairs?

How many connections?

Results

mQTLs in children

Where are the confirmed mQTLs?

model: additive

296 mQTLs (out of 6175) were confirmed in children

Only some of the cis-mQTLs found to be significant in parents were confirmed with the additive model. This plot shows that there is no clustering of those confirmed mQTLs within chromosome 20.

Where are the mQTLs with interaction?

model: interaction

314 mQTLs (out of 6175) had significant interaction with ART-status in children

Only some of the cis-mQTLs found to be significant in parents had significant interaction with ART-status in children. This plot shows that there is no clustering of those mQTLs within chromosome 20.

Zooming in…

Part1

Part2

Part3

Discussion

Extra slides

‘Strongest’ associations, additive model

           SNP       gene   term    estimate   std.error statistic      p.value
        <char>     <char> <char>       <num>       <num>     <num>        <num>
1: rs142527558 cg10797920   SNP1  0.03434030 0.007438696  4.616441 4.187951e-06
2:  rs79359164 cg26680502   SNP1  0.01845339 0.006365479  2.898980 3.790711e-03
3:  rs79033469 cg00794607   SNP1 -0.01758346 0.008407823 -2.091322 3.664345e-02
4:  rs35849074 cg26680502   SNP1  0.01739812 0.006135291  2.835745 4.624445e-03
5: rs188100838 cg26680502   SNP1  0.01596453 0.005673459  2.813898 4.949335e-03
6:   rs8126087 cg20937230   SNP1 -0.01574302 0.007539033 -2.088202 3.692445e-02
       conf.low     conf.high  SNP_pos  CpG_pos
          <num>         <num>    <int>    <int>
1:  0.019750642  0.0489299635 61586712 62495449
2:  0.005968599  0.0309381864 37764667 37433765
3: -0.034073923 -0.0010930005 30953516 30143151
4:  0.005364851  0.0294313831 37659385 37433765
5:  0.004837043  0.0270920202 37462351 37433765
6: -0.030529526 -0.0009565226   976128   725968
           SNP       gene   term     estimate   std.error statistic
        <char>     <char> <char>        <num>       <num>     <num>
1: rs142892531 cg04446876   SNP1 -0.009995664 0.001500043 -6.663587
2:  rs41278236 cg11145914   SNP1 -0.010154342 0.001545462 -6.570425
3:  rs16987038 cg20606255   SNP1  0.011110467 0.001986969  5.591665
4:  rs45555040 cg20606255   SNP1  0.011083456 0.001986446  5.579541
5: rs144117172 cg10817792   SNP1 -0.005553789 0.001184940 -4.686979
6: rs142527558 cg10797920   SNP1  0.034340303 0.007438696  4.616441
        p.value     conf.low    conf.high  SNP_pos  CpG_pos
          <num>        <num>        <num>    <int>    <int>
1: 3.577903e-11 -0.012937746 -0.007053582 59699754 60630424
2: 6.595683e-11 -0.013185485 -0.007123199 62641605 62564447
3: 2.604532e-08  0.007213384  0.015007551 36551349 36839442
4: 2.789096e-08  0.007187401  0.014979512 36794916 36839442
5: 2.988150e-06 -0.007877844 -0.003229734 57292298 57004379
6: 4.187951e-06  0.019750642  0.048929963 61586712 62495449

Volcano plot, additive model

‘Strongest’ associations, interaction model

            SNP       gene                   term    estimate   std.error
         <char>     <char>                 <char>       <num>       <num>
 1: rs142892531 cg04446876 SNP1:case_controlSTART  0.01944484 0.002965239
 2:  rs16987038 cg20606255 SNP1:case_controlSTART -0.02364613 0.003937080
 3:  rs45555040 cg20606255 SNP1:case_controlSTART -0.02352914 0.003936437
 4: rs117654917 cg12204262 SNP1:case_controlSTART  0.02264140 0.004103064
 5: rs144117172 cg10817792 SNP1:case_controlSTART -0.01298584 0.002358332
 6:  rs41278236 cg11145914 SNP1:case_controlSTART -0.01432727 0.003105520
 7: rs142527558 cg10797920 SNP1:case_controlSTART -0.06688452 0.014945962
 8: rs117226334 cg19122601 SNP1:case_controlSTART  0.01394780 0.003153570
 9: rs117696074 cg09453598 SNP1:case_controlSTART  0.01940239 0.004410773
10: rs182484229 cg06448079 SNP1:case_controlSTART  0.01415210 0.003286212
    statistic      p.value     conf.low    conf.high  SNP_pos  CpG_pos
        <num>        <num>        <num>        <num>    <int>    <int>
 1:  6.557597 7.194759e-11  0.013629022  0.025260666 59699754 60630424
 2: -6.006009 2.307551e-09 -0.031368012 -0.015924256 36551349 36839442
 3: -5.977269 2.743626e-09 -0.031249754 -0.015808525 36794916 36839442
 4:  5.518168 3.939374e-08  0.014593963  0.030688837  2106677  1249928
 5: -5.506367 4.209472e-08 -0.017611304 -0.008360381 57292298 57004379
 6: -4.613485 4.247084e-06 -0.020418188 -0.008236356 62641605 62564447
 7: -4.475089 8.130124e-06 -0.096198338 -0.037570694 61586712 62495449
 8:  4.422859 1.034044e-05  0.007762630  0.020132964 55517482 56254598
 9:  4.398864 1.154167e-05  0.010751414  0.028053370 38891003 39288278
10:  4.306509 1.750905e-05  0.007706764  0.020597434 57327746 57565177