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FinnGen UKBB MVP Meta Analysis Step

gentropy.finngen_ukb_mvp_meta.FinngenUkbMvpMetaSummaryStatisticsIngestionStep

FinnGen UK Biobank and Million Veteran Program meta-analysis summary statistics ingestion step.

Process overview

The step performs the following operations:

  1. Prepares FinnGenManifest and EFOCuration.
  2. Builds the StudyIndex.
  3. Reads the raw summary statistics paths from StudyIndex.
  4. Converts source summary statistics from BGZIP into Parquet.
  5. Prepares VariantDirection for allele flipping.
  6. Harmonises SummaryStatistics.
  7. Performs quality control on harmonised SummaryStatistics.
  8. Updates StudyIndex with QC results.
graph TD
    %% --- INPUTS ---
    A1([source_manifest_path]) --> B1
    A2([efo_curation_path]) --> B2
    A3([gnomad_variant_index_path]) --> G1
    A4([Source Summary Statistics in BGZIP format]) --> C3

    %% --- STEP 1: StudyIndex ---
    subgraph "Building studyIndex"
    B1["FinnGenMetaManifest"] --> C1["StudyIndex"]
    B2["EFOMapping"] --> C1
    end

    %% --- STEP 2: Raw Summary Statistics ---
    subgraph "Downloading summary statistics"
    C1 --> C2["List of summary statistics paths"]
    C2 --> C3["Raw summary statistics in parquet format"]
    end

    %% --- STEP 3: Quality Control ---
    subgraph "Variant Annotations"
    G1["VariantIndex"] --> G2["VariantDirection"]
    end

    %% --- STEP 4: Harmonised Summary Statistics ---
    subgraph "Harmonising summary statistics"
    C3 --> D1["Allele flipping"]
    B1 --> D1
    G2 --> D1
    D1 --> D2["Removal of not meta-analysed variants"]
    D2 --> D3["Removal of low imputation score variants"]
    D3 --> D4["Removal of low allele count variants"]
    D4 --> E1["Harmonised summary statistics in parquet format"]
    end

    %% --- STEP 5: QC ---
    subgraph "Summary Statistics QC"
    E1 --> Q1["SummaryStatistics QC"]
    Q1 --> Q2["StudyIndex annotated with QC"]
    C1 --> Q2
    end

    %% --- STYLING ---
    classDef input fill:#f8f8ff,stroke:#555,stroke-width:1px,color:#000;
    classDef output fill:#e7ffe7,stroke:#555,stroke-width:1px,color:#000;

    class A1,A2,A3,A4 input;
    class Q2,E1,Q1 output;
Inputs
  • This step requires the gnomAD variant index to perform the allele flipping during harmonisation.
  • The source_manifest_path should point to a manifest that includes paths to the summary statistics files.
Outputs

This step outputs 4 artifacts:

  • Raw summary statistics in Parquet format.
  • Harmonised summary statistics in Parquet format.
  • Summary statistics QC results in Parquet format.
  • Study Index in parquet format (updated with QC results).
Source code in src/gentropy/finngen_ukb_mvp_meta.py 
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class FinngenUkbMvpMetaSummaryStatisticsIngestionStep:
    """FinnGen UK Biobank and Million Veteran Program meta-analysis summary statistics ingestion step.

    # Process overview

    The step performs the following operations:

    1. Prepares `FinnGenManifest` and `EFOCuration`.
    2. Builds the `StudyIndex`.
    3. Reads the raw summary statistics paths from `StudyIndex`.
    3. Converts **source summary statistics** from _BGZIP_ into _Parquet_.
    4. Prepares `VariantDirection` for allele flipping.
    5. Harmonises `SummaryStatistics`.
    6. Performs quality control on harmonised `SummaryStatistics`.
    7. Updates `StudyIndex` with QC results.

    ``` mermaid
    graph TD
        %% --- INPUTS ---
        A1([source_manifest_path]) --> B1
        A2([efo_curation_path]) --> B2
        A3([gnomad_variant_index_path]) --> G1
        A4([Source Summary Statistics in BGZIP format]) --> C3

        %% --- STEP 1: StudyIndex ---
        subgraph "Building studyIndex"
        B1["FinnGenMetaManifest"] --> C1["StudyIndex"]
        B2["EFOMapping"] --> C1
        end

        %% --- STEP 2: Raw Summary Statistics ---
        subgraph "Downloading summary statistics"
        C1 --> C2["List of summary statistics paths"]
        C2 --> C3["Raw summary statistics in parquet format"]
        end

        %% --- STEP 3: Quality Control ---
        subgraph "Variant Annotations"
        G1["VariantIndex"] --> G2["VariantDirection"]
        end

        %% --- STEP 4: Harmonised Summary Statistics ---
        subgraph "Harmonising summary statistics"
        C3 --> D1["Allele flipping"]
        B1 --> D1
        G2 --> D1
        D1 --> D2["Removal of not meta-analysed variants"]
        D2 --> D3["Removal of low imputation score variants"]
        D3 --> D4["Removal of low allele count variants"]
        D4 --> E1["Harmonised summary statistics in parquet format"]
        end

        %% --- STEP 5: QC ---
        subgraph "Summary Statistics QC"
        E1 --> Q1["SummaryStatistics QC"]
        Q1 --> Q2["StudyIndex annotated with QC"]
        C1 --> Q2
        end

        %% --- STYLING ---
        classDef input fill:#f8f8ff,stroke:#555,stroke-width:1px,color:#000;
        classDef output fill:#e7ffe7,stroke:#555,stroke-width:1px,color:#000;

        class A1,A2,A3,A4 input;
        class Q2,E1,Q1 output;
    ```

    ??? tip "Inputs"
        - [x] This step requires the gnomAD variant index to perform the allele flipping during harmonisation.
        - [x] The `source_manifest_path` should point to a manifest that includes paths to the summary statistics files.

    ??? tip "Outputs"
        This step outputs 4 artifacts:

        - [x] Raw summary statistics in Parquet format.
        - [x] Harmonised summary statistics in Parquet format.
        - [x] Summary statistics QC results in Parquet format.
        - [x] Study Index in parquet format (updated with QC results).

    """

    def __init__(
        self,
        session: Session,
        # Inputs
        source_manifest_path: str,
        efo_curation_path: str,
        gnomad_variant_index_path: str,
        # Outputs
        study_index_output_path: str,
        raw_summary_statistics_output_path: str,
        harmonised_summary_statistics_output_path: str,
        harmonised_summary_statistics_qc_output_path: str,
        # Harmonisation config
        perform_meta_analysis_filter: bool = True,
        imputation_score_threshold: float = 0.8,
        perform_imputation_score_filter: bool = True,
        min_allele_count_threshold: int = 20,
        perform_min_allele_count_filter: bool = True,
        min_allele_frequency_threshold: float = 1e-4,
        perform_min_allele_frequency_filter: bool = False,
        filter_out_ambiguous_variants: bool = False,
        # QC config
        qc_threshold: float = 1e-8,
    ) -> None:
        """Data ingestion and harmonisation step for FinnGen UKB meta-analysis.

        Args:
            session (Session): Session object.
            source_manifest_path (str): Path to the manifest file.
            efo_curation_path (str): Path to the EFO curation file.
            gnomad_variant_index_path (str): Path to the gnomAD variant index file.
            study_index_output_path (str): Output path for the study index.
            raw_summary_statistics_output_path (str): Output path for raw summary statistics.
            harmonised_summary_statistics_output_path (str): Output path for harmonised summary statistics.
            harmonised_summary_statistics_qc_output_path (str): Output path for harmonised summary statistics QC results.
            perform_meta_analysis_filter (bool, optional): Whether to filter non-meta analyzed variants.
            imputation_score_threshold (float, optional): Imputation score threshold.
            perform_imputation_score_filter (bool, optional): Whether to filter low imputation scores.
            min_allele_count_threshold (int, optional): Minimum allele count threshold.
            perform_min_allele_count_filter (bool, optional): Whether to filter low allele counts.
            min_allele_frequency_threshold (float, optional): Minimum allele frequency threshold.
            perform_min_allele_frequency_filter (bool, optional): Whether to filter low allele frequencies.
            filter_out_ambiguous_variants (bool, optional): Whether to filter out ambiguous variants.
            qc_threshold (float, optional): P-value threshold for QC.

        Raises:
            AssertionError: If no summary statistics paths are found in the study index.
        """
        assert qc_threshold < 1.0, "QC threshold should be a p-value less than 1.0."
        sumstat_harmonisation_config: dict[str, Any] = {
            "perform_meta_analysis_filter": perform_meta_analysis_filter,
            "imputation_score_threshold": imputation_score_threshold,
            "perform_imputation_score_filter": perform_imputation_score_filter,
            "min_allele_count_threshold": min_allele_count_threshold,
            "perform_min_allele_count_filter": perform_min_allele_count_filter,
            "min_allele_frequency_threshold": min_allele_frequency_threshold,
            "perform_min_allele_frequency_filter": perform_min_allele_frequency_filter,
            "filter_out_ambiguous_variants": filter_out_ambiguous_variants,
        }

        session.logger.info(f"Reading Finngen manifest from {source_manifest_path}.")
        finngen_manifest = FinnGenMetaManifest.from_path(
            session=session, manifest_path=source_manifest_path
        )
        session.logger.info(f"Building study index for: {finngen_manifest.meta.value}")
        session.logger.info(f"Reading EFO curation from {efo_curation_path}.")
        efo_mapping = EFOMapping.from_path(
            session=session, efo_curation_path=efo_curation_path
        )

        session.logger.info("Creating study index.")
        study_index = FinnGenMetaStudyIndex.from_finngen_manifest(
            manifest=finngen_manifest, efo_mapping=efo_mapping
        )

        session.logger.info("Writing study index.")
        study_index.df.write.mode(session.write_mode).parquet(study_index_output_path)
        session.logger.info(f"Study index written to {study_index_output_path}.")

        session.logger.info("Reading summary statistics paths from manifest.")
        # NOTE: we can rely on the study index to extract the raw summary statistics paths
        # to make sure to only process these summary statistics which are part of the study index.
        # this may not be accurate if the summary statistics source paths were not found in the
        # source manifest.
        source_summary_statistics_paths = study_index.get_summary_statistics_paths()
        assert (
            len(source_summary_statistics_paths) > 0
        ), "No summary statistics paths found in study index."
        session.logger.info(
            f"Found {len(source_summary_statistics_paths)} summary statistics files."
        )

        session.logger.info("Converting raw summary statistics to Parquet format.")
        FinnGenUkbMvpMetaSummaryStatistics.bgzip_to_parquet(
            session=session,
            summary_statistics_list=source_summary_statistics_paths,
            datasource=finngen_manifest.meta,
            raw_summary_statistics_output_path=raw_summary_statistics_output_path,
            n_threads=FinnGenUkbMvpMetaSummaryStatistics.N_THREAD_OPTIMAL,
        )
        session.logger.info("Raw summary statistics conversion completed.")
        session.logger.info(f"Output path: {raw_summary_statistics_output_path}.")

        session.logger.info("Reading gnomAD variant index.")
        gnomad_variant_index = VariantIndex.from_parquet(
            session=session, path=gnomad_variant_index_path
        )

        session.logger.info("Building variant direction annotations.")
        variant_direction = VariantDirection.from_variant_index(
            variant_index=gnomad_variant_index
        )

        session.logger.info("Reading raw summary statistics.")
        raw_summary_statistics = session.spark.read.parquet(
            raw_summary_statistics_output_path
        )

        session.logger.info("Harmonising summary statistics.")
        session.logger.info("Applying the following harmonisation configuration:")
        for key, value in sumstat_harmonisation_config.items():
            session.logger.info(f"  - {key}: {value}")
        harmonised_summary_statistics = FinnGenUkbMvpMetaSummaryStatistics.from_source(
            raw_summary_statistics=raw_summary_statistics,
            finngen_manifest=finngen_manifest,
            variant_annotations=variant_direction,
            **sumstat_harmonisation_config,
        )

        session.logger.info("Writing harmonised summary statistics.")
        harmonised_summary_statistics.df.write.mode(session.write_mode).parquet(
            harmonised_summary_statistics_output_path
        )
        session.logger.info(
            f"Harmonised summary statistics written to {harmonised_summary_statistics_output_path}."
        )

        session.logger.info("Reading harmonised summary statistics for QC.")
        harmonised_summary_statistics = SummaryStatistics.from_parquet(
            session=session, path=harmonised_summary_statistics_output_path
        )
        session.logger.info("Running summary statistics QC.")
        summary_statistics_qc = SummaryStatisticsQC.from_summary_statistics(
            gwas=harmonised_summary_statistics,
            pval_threshold=qc_threshold,
        )

        session.logger.info("Writing summary statistics QC results.")
        summary_statistics_qc.df.repartition(1).write.mode(session.write_mode).parquet(
            harmonised_summary_statistics_qc_output_path
        )
        session.logger.info(
            f"Summary statistics QC results written to {harmonised_summary_statistics_qc_output_path}."
        )

        session.logger.info("Adding qc to the study index.")
        study_index = StudyIndex.from_parquet(
            session=session, path=study_index_output_path
        )
        study_index = study_index.annotate_sumstats_qc(summary_statistics_qc)

        session.logger.info("Writing updated study index.")
        study_index.df.repartition(1).write.mode("overwrite").parquet(
            study_index_output_path
        )
        session.logger.info("Updated study index with qc flags.")

__init__(session: Session, source_manifest_path: str, efo_curation_path: str, gnomad_variant_index_path: str, study_index_output_path: str, raw_summary_statistics_output_path: str, harmonised_summary_statistics_output_path: str, harmonised_summary_statistics_qc_output_path: str, perform_meta_analysis_filter: bool = True, imputation_score_threshold: float = 0.8, perform_imputation_score_filter: bool = True, min_allele_count_threshold: int = 20, perform_min_allele_count_filter: bool = True, min_allele_frequency_threshold: float = 0.0001, perform_min_allele_frequency_filter: bool = False, filter_out_ambiguous_variants: bool = False, qc_threshold: float = 1e-08) -> None

Data ingestion and harmonisation step for FinnGen UKB meta-analysis.

Parameters:

Name Type Description Default
session Session

Session object.

 required
source_manifest_path str

Path to the manifest file.

 required
efo_curation_path str

Path to the EFO curation file.

 required
gnomad_variant_index_path str

Path to the gnomAD variant index file.

 required
study_index_output_path str

Output path for the study index.

 required
raw_summary_statistics_output_path str

Output path for raw summary statistics.

 required
harmonised_summary_statistics_output_path str

Output path for harmonised summary statistics.

 required
harmonised_summary_statistics_qc_output_path str

Output path for harmonised summary statistics QC results.

 required
perform_meta_analysis_filter bool

Whether to filter non-meta analyzed variants.

 True
imputation_score_threshold float

Imputation score threshold.

 0.8
perform_imputation_score_filter bool

Whether to filter low imputation scores.

 True
min_allele_count_threshold int

Minimum allele count threshold.

 20
perform_min_allele_count_filter bool

Whether to filter low allele counts.

 True
min_allele_frequency_threshold float

Minimum allele frequency threshold.

 0.0001
perform_min_allele_frequency_filter bool

Whether to filter low allele frequencies.

 False
filter_out_ambiguous_variants bool

Whether to filter out ambiguous variants.

 False
qc_threshold float

P-value threshold for QC.

 1e-08

Raises:

Type Description
AssertionError

If no summary statistics paths are found in the study index.
Source code in src/gentropy/finngen_ukb_mvp_meta.py 
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def __init__(
    self,
    session: Session,
    # Inputs
    source_manifest_path: str,
    efo_curation_path: str,
    gnomad_variant_index_path: str,
    # Outputs
    study_index_output_path: str,
    raw_summary_statistics_output_path: str,
    harmonised_summary_statistics_output_path: str,
    harmonised_summary_statistics_qc_output_path: str,
    # Harmonisation config
    perform_meta_analysis_filter: bool = True,
    imputation_score_threshold: float = 0.8,
    perform_imputation_score_filter: bool = True,
    min_allele_count_threshold: int = 20,
    perform_min_allele_count_filter: bool = True,
    min_allele_frequency_threshold: float = 1e-4,
    perform_min_allele_frequency_filter: bool = False,
    filter_out_ambiguous_variants: bool = False,
    # QC config
    qc_threshold: float = 1e-8,
) -> None:
    """Data ingestion and harmonisation step for FinnGen UKB meta-analysis.

    Args:
        session (Session): Session object.
        source_manifest_path (str): Path to the manifest file.
        efo_curation_path (str): Path to the EFO curation file.
        gnomad_variant_index_path (str): Path to the gnomAD variant index file.
        study_index_output_path (str): Output path for the study index.
        raw_summary_statistics_output_path (str): Output path for raw summary statistics.
        harmonised_summary_statistics_output_path (str): Output path for harmonised summary statistics.
        harmonised_summary_statistics_qc_output_path (str): Output path for harmonised summary statistics QC results.
        perform_meta_analysis_filter (bool, optional): Whether to filter non-meta analyzed variants.
        imputation_score_threshold (float, optional): Imputation score threshold.
        perform_imputation_score_filter (bool, optional): Whether to filter low imputation scores.
        min_allele_count_threshold (int, optional): Minimum allele count threshold.
        perform_min_allele_count_filter (bool, optional): Whether to filter low allele counts.
        min_allele_frequency_threshold (float, optional): Minimum allele frequency threshold.
        perform_min_allele_frequency_filter (bool, optional): Whether to filter low allele frequencies.
        filter_out_ambiguous_variants (bool, optional): Whether to filter out ambiguous variants.
        qc_threshold (float, optional): P-value threshold for QC.

    Raises:
        AssertionError: If no summary statistics paths are found in the study index.
    """
    assert qc_threshold < 1.0, "QC threshold should be a p-value less than 1.0."
    sumstat_harmonisation_config: dict[str, Any] = {
        "perform_meta_analysis_filter": perform_meta_analysis_filter,
        "imputation_score_threshold": imputation_score_threshold,
        "perform_imputation_score_filter": perform_imputation_score_filter,
        "min_allele_count_threshold": min_allele_count_threshold,
        "perform_min_allele_count_filter": perform_min_allele_count_filter,
        "min_allele_frequency_threshold": min_allele_frequency_threshold,
        "perform_min_allele_frequency_filter": perform_min_allele_frequency_filter,
        "filter_out_ambiguous_variants": filter_out_ambiguous_variants,
    }

    session.logger.info(f"Reading Finngen manifest from {source_manifest_path}.")
    finngen_manifest = FinnGenMetaManifest.from_path(
        session=session, manifest_path=source_manifest_path
    )
    session.logger.info(f"Building study index for: {finngen_manifest.meta.value}")
    session.logger.info(f"Reading EFO curation from {efo_curation_path}.")
    efo_mapping = EFOMapping.from_path(
        session=session, efo_curation_path=efo_curation_path
    )

    session.logger.info("Creating study index.")
    study_index = FinnGenMetaStudyIndex.from_finngen_manifest(
        manifest=finngen_manifest, efo_mapping=efo_mapping
    )

    session.logger.info("Writing study index.")
    study_index.df.write.mode(session.write_mode).parquet(study_index_output_path)
    session.logger.info(f"Study index written to {study_index_output_path}.")

    session.logger.info("Reading summary statistics paths from manifest.")
    # NOTE: we can rely on the study index to extract the raw summary statistics paths
    # to make sure to only process these summary statistics which are part of the study index.
    # this may not be accurate if the summary statistics source paths were not found in the
    # source manifest.
    source_summary_statistics_paths = study_index.get_summary_statistics_paths()
    assert (
        len(source_summary_statistics_paths) > 0
    ), "No summary statistics paths found in study index."
    session.logger.info(
        f"Found {len(source_summary_statistics_paths)} summary statistics files."
    )

    session.logger.info("Converting raw summary statistics to Parquet format.")
    FinnGenUkbMvpMetaSummaryStatistics.bgzip_to_parquet(
        session=session,
        summary_statistics_list=source_summary_statistics_paths,
        datasource=finngen_manifest.meta,
        raw_summary_statistics_output_path=raw_summary_statistics_output_path,
        n_threads=FinnGenUkbMvpMetaSummaryStatistics.N_THREAD_OPTIMAL,
    )
    session.logger.info("Raw summary statistics conversion completed.")
    session.logger.info(f"Output path: {raw_summary_statistics_output_path}.")

    session.logger.info("Reading gnomAD variant index.")
    gnomad_variant_index = VariantIndex.from_parquet(
        session=session, path=gnomad_variant_index_path
    )

    session.logger.info("Building variant direction annotations.")
    variant_direction = VariantDirection.from_variant_index(
        variant_index=gnomad_variant_index
    )

    session.logger.info("Reading raw summary statistics.")
    raw_summary_statistics = session.spark.read.parquet(
        raw_summary_statistics_output_path
    )

    session.logger.info("Harmonising summary statistics.")
    session.logger.info("Applying the following harmonisation configuration:")
    for key, value in sumstat_harmonisation_config.items():
        session.logger.info(f"  - {key}: {value}")
    harmonised_summary_statistics = FinnGenUkbMvpMetaSummaryStatistics.from_source(
        raw_summary_statistics=raw_summary_statistics,
        finngen_manifest=finngen_manifest,
        variant_annotations=variant_direction,
        **sumstat_harmonisation_config,
    )

    session.logger.info("Writing harmonised summary statistics.")
    harmonised_summary_statistics.df.write.mode(session.write_mode).parquet(
        harmonised_summary_statistics_output_path
    )
    session.logger.info(
        f"Harmonised summary statistics written to {harmonised_summary_statistics_output_path}."
    )

    session.logger.info("Reading harmonised summary statistics for QC.")
    harmonised_summary_statistics = SummaryStatistics.from_parquet(
        session=session, path=harmonised_summary_statistics_output_path
    )
    session.logger.info("Running summary statistics QC.")
    summary_statistics_qc = SummaryStatisticsQC.from_summary_statistics(
        gwas=harmonised_summary_statistics,
        pval_threshold=qc_threshold,
    )

    session.logger.info("Writing summary statistics QC results.")
    summary_statistics_qc.df.repartition(1).write.mode(session.write_mode).parquet(
        harmonised_summary_statistics_qc_output_path
    )
    session.logger.info(
        f"Summary statistics QC results written to {harmonised_summary_statistics_qc_output_path}."
    )

    session.logger.info("Adding qc to the study index.")
    study_index = StudyIndex.from_parquet(
        session=session, path=study_index_output_path
    )
    study_index = study_index.annotate_sumstats_qc(summary_statistics_qc)

    session.logger.info("Writing updated study index.")
    study_index.df.repartition(1).write.mode("overwrite").parquet(
        study_index_output_path
    )
    session.logger.info("Updated study index with qc flags.")
  • 2025-10-27
  • 2025-10-27
  • Contributors