Journal club 20210111

count: false
class: left, bottom

# Journal club 
## January 11, 2021

<img src="bristol-logo.png" width="20%">
<img src="ieu-logo.png" width="17%">
---
layout: true

.logo[.mrcieu[
MRC Integrative Epidemiology Unit    
]]

---

## EWAS at birth

.striped[
|     pmid|journal                 |variable                                             |tissue                  |n                      |cohort                   |assocs                                 |notes                                                   |
|--------:|:-----------------------|:----------------------------------------------------|:-----------------------|:------------------------|:----------------------|:------------------------|:--------------------------------------|:-------------------------------------------------------|
| 33406918|Epigenomics             |maternal HbA1c                                       |cord blood              |412                    |Gen3G                    |1                                      |effect direction replicated                             |
| 33324494|Environ Epigenet        |lead exposure                                        |cord blood              |420                    |Mexican pre-birth cohort |none                                   |lead measured in cord blood and maternal blood and bone |
| 33356526|Environ Health Perspect |per- and polyfluroalkyl substances in maternal blood |cord blood              |583                    |                         |1                                      |                                                        |
]

.larger[.center[*These mostly null EWAS sure lead us down.*]]

---

## EWAS in children

.striped[
|     pmid|journal                 |variable                                             |tissue                  |age                      |n                      |cohort                   |assocs                                 |notes                                                   |
|--------:|:-----------------------|:----------------------------------------------------|:-----------------------|:------------------------|:----------------------|:------------------------|:--------------------------------------|:-------------------------------------------------------|
| 33338541|J Allergy Clin Immunol  |childhood allergy                                    |blood                   |4 and 8                  |636 and 821            |MeDALL                   |80                                     |21 replicated                                           |
| 33407823|Clin Epigenetics        |lung function trajectory                             |blood                   |10                       |176 males; 136 females |IOW                      |41 males; 55 female                    |2 male; 1 female replicated in ALSPAC (age 7)           |
| 33396735|Nutrients               |infant feeding                                       |peripheral - cord blood |10                       |221                    |Isle of Wight            |87                                     |                                                        |
| 33331245|Epigenetics             |maternal haemoglobin                                 |cord blood; whole blood |0; childhood;adolescence |3967;1534;1962         |PACE                     |none                                   |                                                        |
]

.ii[ ]
.ii[
*To the authors of the maternal haemoglobin study, 
 we'd like to extend our most sincere coagulations
 for publishing such a bloody good paper.*
]

---

## EWAS of victimization

Remember this E-Risk analysis?

> Marzi et al. 
> *Analysis of DNA Methylation in Young People: Limited Evidence for an 
> Association Between Victimization Stress and Epigenetic Variation in Blood*. 
> Am J Psychiatry. 2018 Jun 1;175(6):517-529.

.popup[.box[
.center[
In the paper acknowledgements: 
"We'd like to thank all the study participants, 
especially Kate and her sister Duplikate."
]]]

---

## EWAS in adults

.striped[
| pmid|journal |variable |tissue |age |n |cohort |assocs |notes |
|--------:|:-----------------------|:----------------------------------------------------|:-----------------------|:------------------------|:----------------------|:------------------------|:--------------------------------------|:-------------------------------------------------------|
| 33319642|Epigenetics |IgA Nephropathy1 |CD19+ B cells |~33 |184 |Chinese adults |3 | |
| 33397400|Genome Med |APOE ε4 vs APOE ε2 carriers2 |blood |~50 |2469 vs 1118 |Generation Scotland |3 (2 DMRs) |high-density lipoprotein cholesterol partial mediator |
| 33354722|Int J Epidemiol |diet quality index |blood |~64 |4355 |Womens Health Initiative |428 |24 replicated |
| 33317634|Clin Epigenetics |age |sperm |18-71 |94 | |150K of 2.65 million |methyl-capture |
]

[1] In IgA Nephropathy, IgA builds up in kidneys.

[2] "The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease, whilst the ε2 allele confers protection."

---

## MethylC-Capture and age in sperm

> Cao M, Shao X, Chan P, Cheung W, Kwan T, Pastinen T, Robaire B. **High-resolution analyses of human sperm dynamic methylome reveal thousands of novel age-related epigenetic alterations**. Clin Epigenetics. 2020 Dec 14;12(1):192.

**Data**
* 48 men age 18-38y
* 46 men age 46-71y
* 2.65 million CpG sites

**Age associations**
* 150K associated CpG sites 
* Hypermethylation tended to be distant from genes
* Hypomethylation tended to be near the TSS
* Enriched in development, neuron projection, differentiation and recognition, and behavior

**Age prediction**
* Top 5K age associations
* 4.43y average error (replication set)

---

.larger[.larger[
.center[Sperm studies tend to consider sperm populations of millions of cells.

If possible, we would prefer to focus on the sperm that 
fertilized the egg.]]]

.larger[.larger[
.center[**
 We call these sperm the "ova achievers".
**
]]]
---

## "Universal" epigenetic inter-individual variation

> Planterose Jiménez B, Liu F, Caliebe A, Montiel González D, Bell JT, Kayser M, Vidaki A. **Equivalent DNA methylation variation between monozygotic co-twins and unrelated individuals reveals universal epigenetic inter-individual dissimilarity**. Genome Biol. 2021 Jan 5;22(1):18.

**Variably methylated CpG sites in twins and unrelated individuals**

**Data** 426 MZ twin pairs at age 18 (E-Risk)
--

.ii[
Identify sites with 
* IQR > 0.07
* ICC > 0.37 (based on [Bose et al. 2014](https://www.ncbi.nlm.nih.gov/pubmed/25239148/))
* Have identically distributed differences between twin pairs and between non-twin pairs

**Result** 333 equivalently variable CpGs (evCpG)
]

.ii[
<img src="evcpgs.jpg" width="100%">
]

---

.larger[.larger[.center[Why does the t-distribution have few friends?]]]

.larger[.larger[.center[**Because, on top if being a bit thick, it's not exactly normal.**]]]

---

## "Universal" variation continued ...

**evCpG sites stable over short time**
* Methylation measured 9 months apart in 6 people
* Profiles cluster by person

**Drift of evCpGs over long time-scales**
* In child dataset (n=333), only 1 site associated with age
* In lifetime dataset (n=727 age 14-94), 122/331 evCpGs associated with age

**Variable in other tissues**
* Variation at 46% of sites replicated in adipose tissue

**Conclusion**
* evCpG sites variance is not due to genotype, error, or drift

**Question**
* *What are these good for?!*

---

.ii[
## Mitochondrial DNA abundance

Hägg S, Jylhävä J, Wang Y, Czene K, Grassmann F. **Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance**. Hum Genet. 2020 Dec 31.

**Data**
295,510 participants in UK Biobank

**MT DNA abundance lower in**
* men
* smokers

**negatively associated with**
* frailty
* age
* BMI
* white and red blood cell counts
* mortality
]

.ii[
<img src="fig1.png" width="120%">
* Black borders indicate p < 0.05
* mL2RMT_* are probes targeting mtDNA
* mL2RMT (median log2 ratio of probes)
* mL2R autosomes (autosomal DNA abundance)
]

---

## Mitochondrial DNA abundance, continued

**Associated with**
inflammation,
cholesterol metabolism,
calcium and phosphate ion homeostasis,
kidney function,
liver function,
glucose metabolism.

---

## Mitochondrial DNA abundance, continued

GWAS identified 50 associated loci
"involved in the immune system, cancer as well as mitochondrial function".

SNP-heritability ~ 8%

---

## Mitochondrial DNA abundance, continued

**Associated with** risk for leukaemia, hematologic diseases and hypertension.

---

## Mitochondrial DNA abundance, continued

Recall that:

Castellani CA, Longchamps RJ, Sumpter JA, et al. **Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs.** Genome Med. 2020;12(1):84.

* mtDNA abundance appears to cause DNA methylation changes at several CpG sites
* These CpG sites are associated with relavent outcomes (CVD, CHD, mortality)

Levine ME, Lu AT, Quach A, et al. **An epigenetic biomarker of aging for lifespan and healthspan**. Aging (Albany NY). 2018;10(4):573-591.

* PhenoAge acceleration is associated with "decreased activation of ... mitochondrial signatures".
* mtDNA abundance was not used to train PhenoAge.

Belsky DW, Caspi A, Arseneault L, et al. **Quantification of the pace of biological aging in humans through a blood test, the DunedinPoAm DNA methylation algorithm**. Elife. 2020;9:e54870.

* mtDNA abundance was not used to train 
[DunedinPoAM](https://elifesciences.org/articles/54870).

---

## Is it time to create a DNA methylation proxy of mtDNA abundance?

--
There can be only one answer:

.center[
<img src="mito.jpg">
]