snipar

snipar (single nucleotide imputation of parents) provides a command line toolbox for family-based analyses in genetics:

• family-GWAS: Perform family-GWAS (FGWAS) with a variety of estimators. snipar can perform family-GWAS using genetic differences between siblings, parent-offspring trios, and increase power through using imputed parental genotypes, which enables inclusion and optimal use of samples with only one parent genotyped and without genotyped parents or siblings. See Simulation Exercise: family-GWAS without imputed parental genotypes and Simulation Exercise: family-GWAS with imputed parental genotypes. The regressions are performed in an efficient linear mixed model that accounts for correlations between siblings and more distant relatives.
• family-PGS analyses: Compute and analyze polygenic scores (PGS) for a set of individuals along with their siblings and parents, using both observed and imputed parental genotypes. snipar can estimate the direct effect (within-family) of a polygenic score: see Simulation Exercise: Polygenic score analyses. It can adjust for the impact of assortative mating on estimates of indirect genetic effects (effects of alleles in parents on offspring mediated through the environment) from family-based PGS analysis: see Simulation Exercise: Polygenic score analyses.
• Imputation of missing parental genotypes: For samples with at least one genotyped sibling and/or parent, but without both parents' genotypes available, snipar can impute missing parental genotypes according to Mendelian laws (Mendelian Imputation) and use these to increase power for family-GWAS and PGS analyses. See Tutorial: imputing-missing-parental-genotypes
• Identity-by-descent (IBD) segments shared by siblings: snipar implements a hidden markov model (HMM) to accurately infer identity-by-descent segments shared between siblings. The output of this is needed for imputation of missing parental genotypes from siblings. See Tutorial: inferring IBD between siblings
• Multi-generational forward simulation with indirect genetic effects and assortative mating: snipar includes a simulation module that performs forward simulation of multiple generations undergoing random and/or assortative mating. The phenotype on which assortment occurs can include indirect genetic effects from parents. Users can input phased haplotypes for the starting generation or artificial haplotypes can be simulated. Output includes a multigenerational pedigree with phenotype values, direct and indirect genetic component values, and plink formatted genotypes for the final two generations along with imputed parental genotypes. See Simulation Exercise
• Estimate correlations between effects: Family-GWAS summary statistics include genome-wide estimates of direct genetic effects (DGEs) — the within-family estimate of the effect of the allele — population effects — as estimated by standard GWAS — and non-transmitted coefficients (NTCs), the coefficients on parents' genotypes. The correlate.py scipt enables efficient estimation of genome-wide correlations between these different classes of effects accounting for sampling errors. See Tutorial: correlations between effects

The above illustrates an end-to-end workflow for performing family-GWAS in snipar, an example of which is given in the Tutorial. Not all steps are necessary for all analyses. For example, family-GWAS (and PGS analyses) can be performed without imputed parental genotypes, requiring only input genotypes in .bed or .bgen format along with pedigree information. Also: imputation for parent-offspring pairs can proceed without IBD inference.

Publications

Please cite at least one of these publications if you use snipar in your work!

The methodologies implemented in snipar are described in the following publications:

Mendelian imputation of parental genotypes improves estimates of direct genetic effects.
Alexander Strudwick Young, SM Nehzati, ..., Augustine Kong.
Describes the method for imputation of missing parental genotypes and family-based GWAS with imputed parental genotypes.
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Estimation of indirect genetic effects and heritability under assortative mating.
Alexander Strudwick Young.
Describes family-PGS analysis with adjustment for the impact of assortative mating on estimates of indirect genetic effects.
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Family-GWAS reveals effects of environment and mating on genetic associations. .
Tammy Tan, H Jayashankar, J Guan, SM Nehzati, M Mir, M Bennett, E Agerbo, ..., Alexander Strudwick Young.
Shows snipar applied to generate family-GWAS summary statistics from 17 different cohorts that are meta-analyzed. Describes the methodology for estimating genome-wide correlations between the different classes of effects estimated by family-GWAS.
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Family-based genome-wide association study designs for increased power and robustness.
Describes additional family-GWAS designs: the unified estimator, which increases power for estimating direct genetic effects in homogeneous samples (typical for GWAS) by including all samples through linear imputation; and the robust estimator, which maximizes power in strongly structured or admixed samples without introducing bias. The linear mixed model used in snipar family-GWAS and PGS analyses is described here.
Junming Guan, T Tan, SM Nehzati, M Bennett, P Turley, DJ Benjamin, Alexander Strudwick Young.
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Documentation

Documentation: https://snipar.rtfd.io/

It is recommended to read the guide: https://snipar.rtfd.io/en/latest/guide.html

And to work through the tutorial (https://snipar.readthedocs.io/en/latest/tutorial.html) and simulation exercise (https://snipar.readthedocs.io/en/latest/simulation.html).

Installing Using pip

snipar currently supports Python 3.7-3.9 on Linux, Windows, and Mac OSX (14.7 and higher). We recommend using a python distribution such as Anaconda 3 (https://store.continuum.io/cshop/anaconda/).

The easiest way to install is using pip:

pip install snipar

Sometimes this may not work because the pip in the system is outdated. You can upgrade your pip using:

  pip install --upgrade pip

Note: installing snipar requires the package bed_reader, which in turn requires Rust. If an error occurs at "Collecting bed-reader ...", please try downloading Rust following the instruction here: https://rust-lang.github.io/rustup/installation/other.html.

Virtual Environment

You may encounter problems with the installation due to Python version incompatability or package conflicts with your existing Python environment. To overcome this, you can try installing in a virtual environment. In a bash shell, this could be done either via the venv Python package or via conda.

To create the venv, use the following commands in your directory of choice: python -m venv path-to-where-you-want-the-virtual-environment-to-be

You can activate and use the environment using

  source path-to-where-you-want-the-virtual-environment-to-be/bin/activate

Alternatively, we recommend using conda:

conda create -n myenv python=3.9
conda activate myenv

Installing From Source

To install from source, clone the git repository, and in the directory containing the snipar source code, at the shell type:

pip install .

Note: installing snipar requires the package bed_reader, which in turn requires Rust. If an error occurs at "Collecting bed-reader ...", please try downloading Rust following the instruction here: https://rust-lang.github.io/rustup/installation/other.html.

Python version incompatibility

snipar does not currently support Python 3.10 or higher due to version incompatibilities of dependencies. To overcome this, see Virtual Environment above.

Apple ARM processor machines

There can be difficulties install snipar on Apple ARM processor machines due to lack of available versions of scientific computing software made for these processors' architectures. A workaround for this is to use Snipar in a docker container.

The following steps will guide you on how to create a suitable container for your M1/M2 MacBook and seamlessly integrate it into a VSCode environment. These steps assume you have little knowledge about Docker, so we will start from scratch.

1. Installing Docker Engine

Ensure that Docker Engine is installed on your machine. If it's already installed, you can skip this step. Otherwise, you can install it by following the instructions provided at the following link:

Install Docker Engine on a MacBook

2. Creating the Docker Container

To install the Snipar package, you need to create a Docker container that emulates a virtual Ubuntu machine where Snipar can be installed.

To create the appropriate Docker container, follow these steps:

• Start the Docker engine. Just open the Docker application from your Applications folder.

• While the engine is running, open your terminal and execute the following command to create a container named "snipar_container" (you can choose a different name if you prefer):

  docker run --name snipar_container -it amd64/python:3.9.9-slim-buster /bin/bash
  

After running this command, you should see the "snipar_container" listed in the Docker GUI under the "Containers" tab.

• You can close the terminal at this point.

3. Running the Container

To use the environment of the created container within VSCode or other IDEs, ensure that the container is running. You can do this easily through the Docker GUI:

• Open the Docker GUI.
• In the "Containers" section of the dashboard, locate "snipar_container" (or the name you chose for your container).
• Click the play button to start the container.

Once the container is running, you can access its terminal and files through the Docker GUI. Keep in mind that the files within the container are isolated from your macOS files. You won't be able to access them using Finder, but you can manage them through the Docker GUI, including uploading and downloading.

4. Attaching the Container to VSCode

If you prefer a smoother development experience with VSCode, follow these steps to attach the container to VSCode:

• Install the "Dev Containers" extension by visiting the following link in the VS Marketplace:

  Dev Containers Extension

• Once installed, a new icon will appear on the left sidebar of VSCode labeled " Remote Explorer."

• Click on "Remote Explorer" and, under the "Dev Containers" section, locate " snipar_container."

• Next to the container name, you'll find a button that says "Attach in a new window." Click on this button, and VSCode will open a new window attached to the container.

In the newly attached VSCode window, the terminal will be connected to the container, similar to the "Exec" tab in the Docker GUI. You can also open folders from the container environment (not your Mac itself) using the "Open Folder" button in VSCode. This makes it more convenient to manage files while writing code, and you can run your modules using the terminal directly within VSCode.

5. Installing snipar Package in the Container

Up to this point, you've set up the environment for snipar but haven't installed it in the container. To install snipar, follow these steps:

• Open the terminal in the VSCode window attached to "snipar_container" (or use the "Exec" tab in the Docker GUI).
• After cloning the git repository and cding into the directory, run the following command:

  pip install .
  

Running tests

To check that the code is working properly and that the C modules have been compiled, you can run the tests using this command:

python -m unittest snipar.tests