Comparative Analysis of Drug-Related Genetic Variant Frequencies Across Populations

Project Overview

This project investigates allele frequency differences in variants known to affect drug response, comparing major populations using data from the gnomAD v4 database. The data-driven approach includes preprocessing of large .vcf.gz files, extracting relevant pharmacogenomic variants, and visualizing allele frequency differences — with a focus on how population genetics may influence drug efficacy.

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Goals & Workflow

Goal 1: Preprocessing gnomAD Data

Description:
gnomAD v4 variant files are extremely large and contain excessive information. The key data of interest — allele frequencies — are stored in the INFO column of the VCF format (column 8).

Solution:
A custom C++ script, shrink_vcf.cpp, was developed to extract only necessary INFO fields (e.g., allele frequency per population). It reads from standard input and outputs streamlined VCF data. This reduced memory usage significantly, allowing storage and processing on machines with limited disk space.

A Makefile rule automates this process when raw data is present. The preprocessed files are not included in this repository due to size, but the method is reproducible by running:

make

Goal 2: Visualizing Population Data as a Matrix

Description:
The aim was to visualize allele frequencies per variant across populations in a matrix-style layout, with rows as populations and columns as genomic positions.

Solution:
JBrowse2 could not support this style for gnomAD summary data, since it’s designed for sample-based datasets. IGV (Integrative Genomics Viewer) was used instead, by splitting VCFs by population and loading them as tracks. Changing the display mode to COLLAPSED allowed simultaneous view of all populations.

Population codes used:

• AFR – African/African American
• AMR – Admixed American
• ASJ – Ashkenazi Jewish
• EAS – East Asian
• FIN – Finnish
• NFE – Non-Finnish European
• SAS – South Asian
• REMAINING – Other / unassigned

Variants are color-coded in IGV based on allele frequency, which provided a useful approximation of a heatmap/matrix.

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Goal 3: Extracting Drug-Associated Variants

Description:
Only specific variants known to affect drug response (listed in rs_dbsnp_joined.tsv) were of interest for downstream analysis.

Solution:
The script collect_freqs_select.py filters preprocessed VCFs and extracts allele frequencies for only those pharmacogenomic variants, grouped by population.

Execution example:

zcat *.vcf.gz | pypy3 collect_freqs_select.py

Or using Make:

make collect

Note: Python scripts were executed with PyPy3 for better performance on large data.

Goal 4: Comparing Non-Finnish Europeans to Other Populations

Description:
The goal was to quantify and visualize the difference in allele frequencies between the Non-Finnish European (NFE) population and others for drug-relevant variants.

Solution:
The script collect_freqs_bg.py computes absolute differences in allele frequencies between NFE and each other population, generating .bedGraph files: nfe-vs-{}.bedGraph. These files can be loaded into IGV to visualize population-specific allele frequency divergence across the genome.

make bedgraphs

Example findings

Chromosome X

• Loc 45,781,104-45,781,104
  Variant: T vs C
  Associated Drugs: Cisplatin, Fluorouracil, Mitoxantrone
  Condition: Hepatocellular carcinoma
  Insight: Allele C is significantly more frequent in East/South Asian, African, and American populations than in Non-Finnish Europeans. Thus, these drugs are more effective in Europeans and may be less effective in other populations.

• Loc 123,183,391-123,183,391
  Genotype: TT vs CC + CT
  Drug: SSRIs or Venlafaxine
  Condition: Major Depressive Disorder
  Insight: The C allele is less frequent in Non-Finnish Europeans. Most Europeans have the TT genotype, making treatment with these antidepressants less effective in this population.

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Chromosome 22

• Loc 41,682,662-41,682,662
  Variant: G vs A
  Drug: Vincristine
  Conditions: Various childhood cancers (e.g., Glioma, Medulloblastoma)
  Insight: G allele is more frequent in Non-Finnish Europeans (and East Asians), indicating that checking vincristine concentrations is more relevant in Europe.

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Chromosome 19

• Loc 13,410,714-13,410,714
  Variant: G vs A
  Drug: Antiepileptics
  Condition: Epilepsy
  Insight: G allele is less frequent in Europeans; majority have AA genotype, indicating better resistance to antiepileptics.

• Loc 11,333,455-11,333,455
  Variant: G vs C
  Drug: Platinum compounds
  Condition: Lung Neoplasms
  Insight: G allele is more common in Europeans (except Ashkenazi Jews). This may hinder drug response.

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Chromosome 18

• Loc 58,227,849-58,227,849
  Variant: C vs G
  Drug: Hydrochlorothiazide
  Condition: Hypertension
  Insight: G allele is less common in Europeans; drug is more effective in this population.

• Loc 58,792,367-58,792,367
  Variant: G vs A
  Drug: Cyclosporine
  Condition: Psoriasis
  Insight: G allele is more frequent in Non-Finnish Europeans than in Africans, Asians, or even Finnish Europeans.

• Loc 4,970,507-4,970,507
  Variant: C vs A
  Drug: SSRIs
  Condition: Major Depressive Disorder
  Insight: C allele is more frequent in Non-Finnish Europeans, potentially reducing effectiveness of SSRIs.

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Chromosome 17

• Loc 61,406,405-61,406,405
  Variant: C vs T
  Drug: Atenolol
  Condition: Hypertension
  Insight: C allele is less frequent in Europeans; T is more frequent, suggesting atenolol is effective.

• Loc 63,488,670-63,488,670
  Genotype: GG vs others
  Drug: Sertraline
  Condition: Major Depressive Disorder
  Insight: A allele is less common in Europeans; majority have GG genotype, suggesting low drug response.

• Loc 46,024,197-46,024,197
  Variant: C vs T
  Drug: Corticosteroids
  Condition: Asthma
  Insight: C allele is frequent in Europeans (second only to Jewish population). May reduce treatment effectiveness.

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Chromosome 16

• Loc 1,202,369-1,202,369
  Variant: T vs C
  Drug: Ethosuximide
  Condition: Epilepsy
  Insight: T allele is less frequent in Europeans; drug is more effective.

• Loc 1,220,162-1,220,162
  Variant: A vs G
  Drug: Antiepileptics
  Condition: Epilepsy
  Insight: A allele is least frequent in Europeans, suggesting greater drug resistance.

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Chromosome 15

• Loc 45,253,280-45,253,280
  Variant: T vs C
  Drug: Tenofovir
  Condition: HIV
  Insight: T allele is most frequent in Europeans, increasing pharmacokinetic risks.

• Loc 45,262,069-45,262,069
  Genotype: AA vs AC + CC
  Drug: Gemcitabine
  Condition: Pancreatic Neoplasms
  Insight: A allele is highly frequent in Europeans; treatment may be less effective.

• Loc 74,785,026-74,785,026
  Variant: C vs A
  Drug: Hydrochlorothiazide
  Condition: Hypertension
  Insight: T allele (likely typo for C) is most frequent in Europeans, making treatment effective.

• Loc 74,751,897-74,751,897
  Variant: A vs G
  Drug: Escitalopram
  Condition: Major Depressive Disorder
  Insight: A allele is much more frequent in Europeans, possibly affecting metabolism.

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Chromosome 14

• Loc 103,699,416-103,699,416
  Variant: A vs G
  Drug: Radiotherapy
  Condition: Nasopharyngeal Neoplasms
  Insight: A allele more frequent in Europeans; treatment may be less effective.

• Loc 90,397,013-90,397,013
  Variant: T vs C
  Drug: Cyclosporine
  Condition: Psoriasis
  Insight: T allele more common in Europeans; drug more effective.

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Chromosome 13

• Loc 20,988,809-20,988,809
  Variant: A vs G
  Drug: Cetuximab
  Condition: Colorectal Neoplasms
  Insight: A allele common in Europeans (~81%); drug less effective.

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Chromosome 12

• Loc 111,446,804-111,446,804
  Variant: T vs C
  Drug: Hydrochlorothiazide
  Condition: Hypertension
  Insight: T allele common in Europeans; reduced treatment effectiveness.

• Loc 111,634,620-111,634,620
  Genotype: AA + AG vs GG
  Insight: G allele less frequent in Europeans; hydrochlorothiazide less effective.

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Chromosome 11

• Loc 126,157,578-126,157,578
  Variant: A vs G
  Drugs: Interferon beta-1a, beta-1b
  Condition: Multiple Sclerosis
  Insight: G allele less frequent in Europeans; better response expected.

• Loc 101,117,303-101,117,303
  Genotypes: CT + TT vs CC
  Drug: Etonogestrel
  Insight: T allele very common in Europeans (~80%); caution advised.

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Chromosome 10

• Loc 107,285,113-107,285,113
  Genotype: GG vs AA + AG
  Drug: Exenatide
  Condition: Type 2 Diabetes
  Insight: G allele common in Europeans; drug more effective.

• Loc 62,045,858-62,045,858
  Variant: C vs T
  Drug: Methotrexate
  Condition: Leukemia
  Insight: C allele rare in Europeans; good diagnostic marker.

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Chromosome 9

• Loc 85,025,721-85,025,721
  Genotype: AA
  Drug: Lithium
  Condition: Bipolar Disorder
  Insight: A allele less frequent in Europeans; lower response expected.

• Loc 100,301,363-100,301,363
  Variant: G vs A
  Drug: Duloxetine
  Condition: Major Depressive Disorder
  Insight: G allele rare in Europeans; lower drug effectiveness.

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Chromosome 7

• Loc 99,647,457-99,647,457
  Variant: C vs A
  Drug: Tacrolimus
  Condition: Kidney Transplant
  Insight: C allele less frequent in Europeans; immune responses less likely.

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Chromosome 6

• Loc 154,117,494-154,117,494
  Variant 1: C vs A (Opioids)
  Variant 2: G vs A (Ethanol)
  Gene: OPRM1
  Insight: Variants are common in Europeans and may reduce sensitivity to opioids and alcohol, suggesting evolutionary adaptation.

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Chromosome 5

• Loc 132,660,151-132,660,151
  Variant: T vs C
  Drug: Hepatitis vaccines
  Insight: C allele common in Europeans (~80%), possibly due to early vaccination campaigns.

• Loc 132,660,808-132,660,808
  Genotypes: AA + AC vs CC
  Drug: Ustekinumab
  Condition: Psoriasis
  Insight: CC genotype common in Europeans; treatment effective.

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Chromosome 4

• Loc 14,788,854-14,788,854
  Variant: G vs A
  Drug: Duloxetine
  Condition: Major Depressive Disorder
  Insight: G allele rare in Europeans; drug less effective.

• Loc 61,914,104-61,914,104
  Genotypes: AG + GG vs AA
  Drug: Methylphenidate
  Condition: ADHD
  Insight: G allele common in Europeans; drug more effective.

• Loc 61,828,999-61,828,999
  Genotype: AA vs AT + TT
  Condition: ADHD
  Insight: A allele less common in Europeans; reinforces above.

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Chromosome 3

• Loc 54,220,102-54,220,102
  Genotype: AA vs GG
  Drug: Antipsychotics
  Condition: Schizophrenia
  Insight: A allele rare in Europeans; treatment more difficult.

• Loc 14,801,652-14,801,652
  Variant: A vs C
  Drugs: Atenolol, Metoprolol
  Condition: Hypertension
  Insight: A allele less frequent in Europeans; lower efficacy.

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Chromosome 2

• Loc 233,916,448-233,916,448
  Variant: C vs T
  Drug: Botulinum toxin A
  Condition: Migraine (Women)
  Insight: C allele rare in Europeans; higher risk of side effects.

• Loc 60,908,994-60,908,994
  Variant: T vs G
  Drug: TNF-alpha inhibitors
  Condition: Rheumatoid Arthritis
  Insight: T allele more common in Europeans; better treatment outcomes.

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Chromosome 1

• Loc 156,882,671-156,882,671
  Genotypes: AC + CC vs AA
  Drugs: Aspirin, Prasugrel
  Insight: C allele is common in Europeans (~73%); weaker drug response.

• Loc 32,290,838-32,290,838
  Genotype: CC vs CT + TT
  Drug: Corticosteroids
  Condition: Asthma (children)
  Insight: C allele less common in Non-Finnish Europeans; treatment effective.

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Requirements

• g++ for compiling shrink_vcf.cpp
• PyPy3 (recommended) or CPython 3.x
• IGV for visualization
• make, zcat, and standard UNIX tools

Licence

This project is open for academic and research use. No license restrictions, but please credit the author and cite the data source: gnomAD v4.