Understanding genetic risk factors �for Long COVID

Hanna M. Ollila

PhD

​

Dec 15 2022

�

LONG COVID symptomatology

Shortness of breath

Brain fog

Depression, Anxiety

Pain

Fatigue

Disturbed sleep

Lack of Smell&taste

Post-exertional malaise 

Microclots and dysregulated coagulation

Tissue destruction

Persistent infection

Autoimmunity and epitope spreading

POSSIBLE PATHOPHYSIOLOGY

Reactivation of EBV or Varicella

Infections as risk factors for later disease

EBV

Influenza / Pandemrix

Streptococcus

VZV/Chickenpox

Flu / Infection

HPV

HIV

Post-viral fatigue syndrome

Multiple sclerosis

Narcolepsy

Rheumatic fever

Shingles

Cervical cancer

Cancers (via immune suppr.)

SARS-COV-2/�COVID-19

Long COVID, �MIS-C, Multisystem inflammatory syndrome in children

Long COVID

• Names
• Post-COVID Condition, PASC, Long COVID
• Prevalence
• Estimated 5-15% of infected
• ICD10 codes: U08 and U09
• WHO:
• Symptoms last 2 months or more
• 3 months from the onset of COVID-19
• Cannot be explained by an alternative diagnosis

​

​

AIMS & RESEARCH QUESTIONS

Identify genetic risk factors for Long COVID

​

Understand biological mechanisms

​

Understand comorbidities and risk factors

​

​

​

​

​

7

COVID-19 positive

Population control

Long COVID

Everyone except people with �long COVID

No

Long COVID

• Recovered in 3 mo

1

2

Population

8

INTERNATIONAL �LONG COVID HGI COLLABORATION

N = 6,450 Long COVID

N = 45,000 COVID-19+ controls

N = 1M population controls

Data Freeze 4

September 2022

*

Population

controls

COVID positive

recovered

controls

Long COVID

and �Test verified

COVID-19

Long COVID

and

Any

COVID-19

Phenotypes

FOXP4 rs9367106 variant

Tomoko Nakanishi

Allele frequency

19%

9%

36%

7%

1-2%

Variants filtered:

• MAF >= 1%
• Imputation INFO > 0.6

and non-Eur ancestry

Long COVID after test verified COVID-19

Long COVID after any COVID-19

rs9367106

rs9367106

Dashed lines represent a proxy variant

• Lung pathophysiology
• Increased FOXP4 expression in lung tissue associated with COVID-19 severity
• Variant associates with adenocarcinoma & interstitial lung disease
• Immune modulator

​

FOXP4 function

References:�D’Antonio et al., Cell Reports, 2021, Wang et al, Hum Mol Genet, 2016; Dai et al, Lancet Respir Med, 2019; Manichaikul et al, Respir Res, 2017)

FOXP4 Gene level pheWAS with other traits

Sleep traits

Immune traits

Traits sorted by category and P-value

Genetic correlation and �Mendelian randomization

Test verified

Test verified

Any COVID

Any COVID

Within COVID

Population controls

Within COVID

Population controls

Within COVID

Population controls

Within COVID

Population controls

Shea Andrews

COVID severity

COVID susceptibility

FOXP4

FOXP4 locus is associated with COVID severity

COVID hospitalization as a risk factor for Long COVID

Two-sample Mendelian randomization, P pleiotropy = 0.95

• Summary

• Mendelian randomization suggests COVID hospitalization increases the risk for Long COVID

• FOXP4 associates with Long COVID

ACKNOWLEDGEMENTS

​

Vilma Lammi, FIMM, FinnGen study

Samuel Jones, FIMM, University of Helsinki

Tomoko Nakanishi and Brent Richards, McGill, Canada

George Davey Smith, Bristol, UK – ALSPAC study

�Eva Schulte, Hugo Zeberg, Michael Hultström, �Minttu Marttila, Betty Cortes, Axel Schmidt, �Abdou Mousas, Ruth Mitchell, Nicholas Timpson, �Massimo Mangino, Shefali Verma�+ many more around the world

​

Andrea Ganna, Mark Daly, FIMM & Broad Institute, �COVID-19 Host Genetics Initiative

​

Join us? vilma.lammi@helsinki.fi

ALSPAC, BoSCO, BQC19, C19-GenoNet, CHIRP, COMRI, COVID-19 Ioannina Biobank, EstBB, EXCEED, FinnGen, GCAT, GEN-COVID, Genotek, Helix, INCMNSZ, IrCOVID, JAPAN COVID-19 Task Force, LifeLines, MoBa, Mount Sinai COVID-19 Biobank, PMBB, Sano GOLD study, SweCOVID, The Danish Blood Donor Study, TiKoCo, TwinsUK, UKB, Understanding Society, COVID-19 cohort in LGDB

INTERNATIONAL �LONG COVID HGI COLLABORATION

N = 6450 Long COVID

N = 45,000 COVID-19+ controls

N = 1M population controls

North America:�BQC19, Canada

​

Helix, US�Mt Sinai, US�PMBB, US

​

INCMNSZ, Mexico

Europe: �FinnGen, Finland N

BoSCO, Germany

DBDS, Denmark

GCAT, Spain

Ioannina, Greece N

TwinsUK

UKBB, UK

EXCEED, UK

Underst. Society, UK

ALSPAC, UK

Genotek, Russia

SweCOVID, Sweden

COMRI, Germany�MoBa, Norway�Lifelines, Netherlands

GEN-COVID, Italy

Data Freeze 4

September 2022

Asia:

IrCOVID, Iran

Japan COVID, Japan

Want to join? Email vilma.lammi�@helsinki.fi

COVID+ control

6 407 LC

46 208

DF4 Meta-analysis

Long COVID (narrow)

23 studies

Long COVID (wide)

Within-COVID

Population-controlled

chr6

6 450 LC

Pop ctrl �1 093 995

24 studies

COVID+ control

2 975 LC

37 935

11 studies

3 018 LC

Pop ctrl �994 582

12 studies

-logP

COVID-19 positive

Population control

Long COVID

Everyone except long COVID cases

No

Long COVID

• Recovered in 3 mo

1

2

Population