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R10

Introduction

FinnGen research project is a public-private partnership combining genotype data from Finnish biobanks and digital health record data from Finnish health registries. FinnGen provides a unique opportunity to study genetic variation in relation to disease trajectories in an isolated population.

FinnGen is a growing project, aiming at 500,000 individuals in the end of 2023.

FinnGen results are subjected to one year embargo and, after that, available to the larger scientific community via the Pheweb browser or through data download.

Data download

To download FinnGen summary statistics you will need to fill the online form at this link. You will then receive an email containing the detailed instructions for downloading the data.

Release 10 contains

GWAS summary association statistics
Fine-mapping results
Variant annotation
HLA region analysis
pQTL analysis
LoF variant burden test results

Using FinnGen data for publications

When using these results in publications, please remember to:

1) Acknowledge the FinnGen study. You can use the following text:

“We want to acknowledge the participants and investigators of the FinnGen study”

2) Cite our latest publication:

Kurki M.I., et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 2023 Jan;613(7944):508-518. doi: 10.1038/s41586-022-05473-8. Epub 2023 Jan 18.

Furthermore, if possible, include "FinnGen" as a keyword for your publication.

If you want to cite this website, use the following citation:

@online{finngen,
  author = {FinnGen},
  title = {{FinnGen} Documentation of R10 release},
  year = 2023,
  url = {https://finngen.gitbook.io/documentation/},
  urldate = {YYYY-MM-DD}
}

Manifest

The manifest file with the link to all the downloadable summary stats is available at:

Data description

File naming pattern and file structure

Summary association statistics

GWAS summary statistics (tab-delimited, bgzipped, genome build 38, index files included) are named as {endpoint}.gz. For example, endpoint I9_CHD has I9_CHD.gz and I9_CHD.gz.tbi.

To learn more about the methods used, see section .

The {endpoint}.gz have the following structure:

Fine-mapping results

Two fine-mapping methods were used:

Fine-mapping results are tab-delimited and bgzipped.

SuSiE results have the following filename pattern:

{endpoint}.SUSIE.cred.bgz
{endpoint}.SUSIE.cred_99.bgz
{endpoint}.SUSIE.snp.bgz

FINEMAP results have the following filename pattern:

{endpoint}.FINEMAP.config.bgz
{endpoint}.FINEMAP.region.bgz
{endpoint}.FINEMAP.snp.bgz

{endpoint}.SUSIE.cred.bgz contain credible set summaries from SuSiE fine-mapping for all genome-wide significant regions. {endpoint}.SUSIE.cred_99.bgz contain the 99% credible set summaries while the default is 95%. They have the following structure:

{endpoint}.SUSIE.snp.bgz contain variant summaries with credible set information and have the following structure:

{endpoint}.FINEMAP.config.bgz contain summary fine-mapping variant configurations from FINEMAP method and have the following structure:

{endpoint}.FINEMAP.region.bgz contain summary statistics on number of independent signals in each region and have the following structure:

{endpoint}.FINEMAP.snp.bgz has summary statistics of variants and into what credible set they may belong to. Columns:

pQTL summary statistics

The {probeName}.gz have the following structure:

LD estimation

ldstore --bcor FG_LD_chr1.bcor --incl-range 20000000-50000000 --table output_file_name.table

Variant annotation

The variant annotation has measures (HWE, INFO, ...) listed per batch.

Data releases

Timeline for releases:

[1] samples used for PheWAS.

How to cite

Please use the following description when referring to our project:

The FinnGen study is a large-scale genomics initiative that has analyzed over 500,000 Finnish biobank samples and correlated genetic variation with health data to understand disease mechanisms and predispositions. The project is a collaboration between research organisations and biobanks within Finland and international industry partners.

When using these results in publications, please remember to:

Acknowledge the FinnGen study. You can use the following text:

“We want to acknowledge the participants and investigators of the FinnGen study”

Cite our latest publication:

Kurki, M.I., Karjalainen, J., Palta, P. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508–518 (2023). https://doi.org/10.1038/s41586-022-05473-8

Furthermore, if possible, include "FinnGen" as a keyword for your publication.

If you want to cite this website, use the following citation:

Methods

Participating biobanks/cohorts

Genotypes

FinnGen individuals were with Illumina and Affymetrix chip arrays (Illumina Inc., San Diego, and Thermo Fisher Scientific, Santa Clara, CA, USA).

Chip genotype data were using the population-specific of 8,554 whole genomes.

Merged imputed genotype data is composed of 116 data sets that include samples from multiple cohorts.

Total number of individuals: 430,897
Total number of variants (merged set): 21,311,942
Reference assembly: GRCh38/hg38

Genotype data

Chip genotype data processing and QC Samples were genotyped with Illumina (Illumina Inc., San Diego, CA, USA) and Affymetrix arrays (Thermo Fisher Scientific, Santa Clara, CA, USA).

Genotype calls were made with GenCall and zCall algorithms for Illumina and AxiomGT1 algorithm for Affymetrix data.

Chip genotyping data produced with previous chip platforms and reference genome builds were lifted over to build version 38 (GRCh38/hg38) following the protocol described here:

Quality control

In sample-wise quality control steps, individuals with ambiguous gender, high genotype missingness (>5%), excess heterozygosity (+-4SD) and non-Finnish ancestry were excluded. In variant-wise quality control steps, variants with high missingness (>2%), low HWE P-value (<1e-6) and low minor allele count (MAC<3) were excluded.

Pre-phasing

Before imputation, chip-genotyped samples were pre-phased with using the default parameters, except the number of conditioning haplotypes, which was set to 20,000.

Genotype imputation

Genotype imputation was done with the population-specific SISu v4.2 reference panel.

The reference panel variant call set was produced with the GATK HaplotypeCaller algorithm by following GATK best practices for variant calling.

Genotype-, sample- and variant-wise QC was carried out iteratively by using the Hail framework v0.2 and the resulting high-quality WGS data for 8,554 individuals were phased with Eagle 2.3.5 as described in the previous section.

Genotype imputation was carried out by using the population-specific SISu v4.2 imputation reference panel with Beagle 4.1 (version 27Jan18.7e1) as described in the following protocol: dx.doi.org/10.17504/protocols.io.xbgfijw.

Post-imputation quality control involved checking the expected conformity of the imputation INFO-value distribution, MAF differences between the target dataset and the imputation reference panel and checking chromosomal continuity of the imputed genotype calls.

SISu reference panel

v4.2 consists of 8,554 WGS of Finnish individuals from 5 research cohorts from:

METSIM (PIs Markku Laakso and Mike Boehnke)
FINRISK (PI Pekka Jousilahti)
Corogene (PI Juha Sinisalo)
Biobank of Eastern Finland (PI Arto Mannermaa)
Finnish EUFAM Dyslipidemia Study (PIs Marja-Riitta Taskinen and Samuli Ripatti)

High-coverage (25x) WGS data used to develop the SISu v4.2 reference panel were generated at the McDonnell Genome Institute at Washington University (PIs Ira Hall and Nathan Stitziel).

Software used

Hail v0.2
Cromwell-42
Wdltool-0.14
Plink 1.9 and 2.0
BCFtools 1.7 and 1.9
Eagle 2.3.5
Beagle 4.1 (version 27Jan18.7e1)
R 3.4.1 (packages: data.table 1.10.4, sm 2.2-5.4)

LD estimation

The files were created using from the Finnish panel v4.2.

The panel has been divided per chromosome. For example, to use the LD information in the first chromosome, FG_LD_chr1.bcor would be the file to use.

Settings used

number of samples: 3775
window size: 1500 kb
accuracy: low
number of threads: 96
LD threshold to include correlations: 0.05

Example usage

can be downloaded via:

And an example to extract variant range 20 Mb - 50 Mb from chromosome 7 is as follows:

Note

It is not preferred to use these LD estimate files for e.g. fine-mapping, since many of the fine-mapping methods (e.g. SuSiE) require in-sample LD information for good results!

Endpoints

Registries

The disease endpoints were defined using nationwide registries:

We harmonized over the International Classification of Diseases (ICD) revisions 8, 9 and 10, cancer-specific ICD-O-3, (NOMESCO) procedure codes, Finnish-specific Social Insurance Institute (KELA) drug reimbursement codes and ATC-codes.

These registries spanning decades were electronically linked to the cohort baseline data using the unique national personal identification numbers assigned to all Finnish citizens and residents.

A full list of FinnGen endpoints is for release 10.

Excluded endpoints

The endpoints with fewer than 50 cases, and developmental “helper” endpoints were excluded from the final PheWas (“OMIT” tag in the endpoint definition file).

Risteys

GWAS

We used regenie for release 10. Regenie's main advantages are fast leave-one-chromosome-out relatedness calculation which avoids proximal contamination, and use of an approximate Firth test which gives more reliable effect size estimates for rare variants.

We used regenie version 2.2.4.

Links:

We analyzed:

2,408 endpoints
- 2,405 binary endpoints
- 3 quantitative endpoints (HEIGHT_IRN, WEIGHT_IRN, BMI_IRN)
412,181 samples
- 230,310 females
- 181,871 males
21,311,942 variants

We included the following covariates in the model: sex, age, 10 PCs, Finngen chip version 1 or 2 , and legacy genotyping batch.

Sample QC and PCA

This is a description of the quality control procedures applied before running the GWAS.

PCA

The PCA for population structure has been run in the following way:

Variant filtering and LD pruning

The sisu version 4.2 imputation panel is pruned iteratively, until a target number of SNPs is reached:

9,641,808 starting variants: only variants with a minimum info score of 0.9 in all batches are kept.

The script starts with [500.0, 50.0, 0.9] params in plink (window,step,r2). It then decreases 0.05 in r2 iteratively pruning the imputation panel until the threshold of 200,000 snps is reached. Once the SNP count falls under 200,000 the closest pruning is returned.

If the higher r2 is closer, 200,000 snps are randomly selected, else the last pruned snps are returned.

Plink flags used: --snps-only --chr 1-22 --max-alleles 2 --maf 0.01 .

For this run 180,037 snps are returned.

PCA outlier detection

Then, FinnGen data was merged with the 1k genome project (1kgp) data, using the variants mentioned above. A round of PCA was performed and a bayesian algorithm was used to spot outliers. This process got rid of 14,547 FinnGen samples. The figure below shows the scatter plots for the first 3 PCs. Outliers, in green, are separated from the FinnGen red cluster.

While the method automatically detected as being outliers the 1kg samples with non European and southern European ancestries, it did not manage to exclude some samples with Western European origins. Since the signal from these samples would have been too small to allow a second round to be performed without detecting substructures of the Finnish population, another approach was used. The FinnGen samples that survived the first round were used to compute another PCA. The EUR and FIN 1kg samples were then projected onto the space generated by the first 3 PCs. Then, the centroid of each cluster was calculated and used to calculate the squared mahalanobis distance of each FinnGen sample to each of the centroids. Being the squared distance a sum of squared variables (with unitary variance, due to the mahalanobis distance), we could see it as a sum of 3 independent squared variables. This allowed us to map the squared distance into a probability (chi squared with 3 degrees of freedom). Therefore, for each cluster, a probability of being part of it was computed. Then, a threshold of 0.95 was used to exclude FinnGen samples whose relative chance of being part of the Finnish cluster was below the level. This method produced another 43 outliers. The figure below shows the first three principal components.

FIN 1kg samples are in purple, while EUR 1kgp samples are in Blue. Samples in green are FinnGen samples who are flagged as being non Finnish, while red ones are considered Finnish.

Kinship

Then all pairs of FinnGen samples up to second degree were returned. The figure below shows the distribution of kinship values.

Then, the previously defined “non Finnish” samples were excluded and 2 algorithms were used to return a unique subset of unrelated samples:

one called greedy would continuously remove the highest degree node from the network of relations, until no more links are left in the network.
one called native, based on a native implementation of python’s networkx package, performed on each subgraph of the network.

The largest independent set of either algorithm would be used to keep those sample, while flagging the others as “outliers” for the final PCA.

Then, the subset of outliers who also belong to the set of duplicates/twins was identified.

Final PCA

To compute the final step the Finngen samples were ultimately separated in three groups:

259,801 inliers: unrelated samples with Finnish ancestry.
153,927 outliers: non duplicate samples with Finnish ancestries, but who are also related to the inliers.
17,169 rejected samples: either of non Finnish ancestry or are twins/duplicates with relations to other samples.

Finally, the PCA for the inliers was calculated, and then outliers were projected on the same PC space, allowing to calculate covariates for a total of 413,728 samples.

Sample filtering based on phenotype data

Of the 413,728 non-duplicate population inlier samples from PCA, we excluded 1,543 samples from analysis because of missing minimum phenotype data, and 5 samples because of failing sex check with F thresholds of 0.4 and 0.7. A total of 412,181 samples were used for core analysis. There are 230,310 females and 181,871 males among these samples.

Further info

Bayesian outlier detection

Association tests

Endpoint

We included 2,408 endpoints in the analysis, which consisted of 2,405 binary endpoints and 3 quantitative endpoints (HEIGHT_IRN, WEIGHT_IRN, BMI_IRN). Endpoints with less than 50 cases among the 412,181 samples were excluded, as well as endpoints labeled with an OMIT tag in the endpoint definition file.

The quantitative endpoints HEIGHT and WEIGHT were acquired from minimum phenotype data. After that, phenotype BMI was formed from them, and all of them were inverse normal transformed.

Null models

For regenie step 1 LOCO prediction computation for each endpoint, we used age, sex, 10 PCs, Finngen 1 or 2 chip or legacy genotyping batch as covariates. For sex-specific phenotypes, sample sex was left out from the covariates. We excluded covariates that had less than 10 cases.

For calculating genetic relatedness in regenie step 1, we included variants 1) imputed with an INFO score > 0.95 in all batches and 2) > 97 % non-missing genotypes and 3) MAF > 1 %. The remaining variants were LD pruned with a 1.5Mb window and r2 threshold of 0.2. This resulted in a set of 228,119 well-imputed not rare variants for relatedness calculation.

We used a genotype block size of 1,000 in regenie step 1.

Association tests

We ran association tests with regenie for each of the 2,408 endpoints for each variant with a minimum allele count of 5 among each phenotype’s cases and controls. We used the approximate Firth test for variants with an initial p-value of less than 0.01 and computed the standard error based on effect size and likelihood ratio test p-value (regenie options --firth --approx --pThresh 0.01 --firth-se).

LoF variant burden

Gene-based burden test results of loss of function variants (LoFs).

Variant Selection

Loss of function (LoF) variants were generated from vcf files with VEP (https://github.com/Ensembl/ensembl-vep). LoF variants are defined as having consequences in the list [frameshift_variant,splice_donor_variant,stop_gained,splice_acceptor_variant]. Also, a max_maf (0.01) and minimum info score (0.8) filters are applied. This left us with 579 genes with 2+ LoF variants that can be used for the association tests.

Endpoint

We used 2,405 binary phenotypes in the analyses.

Null Models

We used as inputs the nulls already calculated for GWAS

Association tests

Tests are performed with regenie --step2 in burden mode using a max mask (i.e. using the maximum number of ALT alleles across sites)

Fine-mapping

We used two state-of-the-art methods, FINEMAP (Benner, C. et al., 2016; Benner, C. et al., 2018) and SuSiE (Wang, G. et al., 2020) to fine-map genome-wide significant loci in FinnGen endpoints.

Briefly, there are three main steps:

1. Preprocessing

For each genome-wide significant locus (default configuration: P < 5e-8), we define a fine-mapping region by taking a 3 Mb window around a lead variant (and merge regions if they overlap). If a merged window exceeds 10MB, we iteratively shrink the window by 10%, until the merged window fits into 10MB or is split into merged windows that each fit into 10MB. We preprocess an input GWAS summary statistics into separate files per region for the following steps.

2. LD computation

We compute in-sample dosage LD using LDstore2 for each fine-mapping region.

3. Fine-mapping

With the inputs of summary statistics and in-sample LD from the steps 1-2, we conduct fine-mapping using FINEMAP and SuSiE with the maximum number of causal variants in a locus L = 10.

Notes

Due to too many variants and too large LD regions the following endpoints were run with a refined region selection algorithm that limits the region's size to a set maximum length:

G6_MUSDYST
G6_MYONEU
Q17_CONGEN_MALFO_GALLB_BILE_DUCTS_LIVER
Q17_OTHER_CONGEN_MALFO_DIGES_SYSTEM1
Q17_OTHER_CONGEN_MALFO_SKIN
RX_STATIN
BMI_IRN
HEIGHT_IRN

Integration to PheWeb

The "Credible Sets"-table on a phenotype page in the R10 PheWeb browser shows the SuSiE-fine-mapped credible sets of that phenotype. The variant shown per credible set is the maximum PIP (posterior inclusion probability) variant of that credible set. In addition to the causal variants, variants that were in sufficient LD (Pearson r^2 > 0.05), had a small enough p-value (pval < 0.01), and were close enough to the lead variant (distance to lead variant < 1.5 megabases) were clumped together with the credible set. Variants have been compared against GWAS Catalog and annotated. The LD grouping, annotation and GWAS Catalog comparison were done using the autoreporting pipeline.

The columns of the table are explained below:

pQTL analysis

FINNGEN PROTEOMICS SUMMARY STATISTICS

General description

Compiled summary stats for proteomics QTL in imputed SNPs on FINNGEN. Two platforms are included, Olink (619 samples across 2925 proteins) and SomaScan (828 samples across 7596 proteins).

pQTL: The association results are from PLINK2 and in unrelated samples only (Relatedness cutoff based on genotype correlation r > 0.0625 for HapMap3 SNPs). Due to different sample size, the SNP set are not same between those two dataset.
Finemap: see Fine-mapping page, we input the summary data from pQTL
autoreporting: annotation of independent hits lead variants with e.g. gwas catalog, putative causal coding variants in credible set, gnomad allele frequencies

See the "Software" section for the software or pipeline we used.

Data

Folder structure

/Somascan: from Somascan V4.1 assay, 828 unrelated samples from R12 imputed genotype

/Olink: from Olink Explore 3072 library, 619 unrelated samples from R12 imputed genotype

/pQTL:  proteomics QTL via PLINK2 with pre-adjusted age, sex, batch variables and 5PCs, then rank-based inverse normal transformed.

    Files:  ${PROBE_NAME}.txt.gz, bgzipped summary statistics.

            ${PROBE_NAME}.txt.gz.tbi, tabix index without the header line.


/Finemap:  Finemap of the pQTL results above for SNPs with MAC > 8
    FINEMAP: finemapping results from FINEMAP
    - all: all results
    - filter: filtered results

    Susie: finemapping results from Susie
    - all: all results
    - filter: filtered results

/autoreporting:
    Filter and group genome-wide significant variants from FinnGen summary statistics
    Annotate the genome-wide significant variants using gnomAD and FinnGen annotations.
    - group_report: grouped results by phenotype
    - variant_report: results for each variant

Column descriptions for pQTL results

Map the probes's name to gene symbol

File: all_gene_info.txt

Olink: Other annotations from Olink as indicated by the column name.
Somascan: Other annotations from SomaScan as indicated by the column name. Note: NA means no matching, but keep the probe in the data to be complete.

Software

Assocation: PLINK2 v2.00a3.3LM AVX2 Intel (3 Jun 2022)
Finemap: FINNGEN/finemapping-pipeline, revised on R10, hash e0792ea
Coloc: FINNGEN/colocalization, revised on R10, hash 2e0632c
Autoreporting: FINNGEN/autoreporting, revised on hash 9dbea66

HLA region analysis

HLA imputation

The HLA data was imputed from R10 genotype data, using HIBAG models created by Jarmo Ritari from the Finnish Blood Bank. More information can be found in the repository:

https://github.com/FRCBS/HLA-imputation

as well as in the publication:

Ritari J, Hyvä rinen K, Clancy J, FinnGen, Partanen J, Koskela S. Increasing accuracy of HLA imputation by a population-specific reference panel in a Finngen biobank cohort. NAR Genomics and Bioinformatics, Volume 2, Issue 2, June 2020, lqaa030, https://doi.org/10.1093/nargab/lqaa030

Genotype data was constructed from the dosage data using PLINK 2.

Variant summary

A snp-stats report was generated with qctool

Association testing

Association testing was performed using Regenie 2.2.4. Same settings were used as in the core GWAS analysis. See the Association tests page for more information.

Association summary

A summary was created from the regenie summary statistic outputs. This summary contains the most significant variant (by p-value) for each phenotype. Pheweb links to phenotype and gene pages have been added as additional columns.

Contact

For matters related to this documentation, send us an email to finngen-info@helsinki.fi.

for the latest updates on the project as well as additional background information please consider visiting the study website https://www.finngen.fi/en or follow FinnGen on twitter @FinnGen_FI.

If you want to host FinnGen summary statistics on your website, please get in contact with us at: humgen-servicedesk@helsinki.fi.