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Natural genetic variation as a discovery platform for human immunology and hematopoiesis

Ali, Zain LU (2026) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Blood and immune cell traits vary continuously between healthy individuals and are largely heritable, making them tractable to genome-wide association analysis. The variants they implicate are mostly non-coding, and their target genes, mechanisms and cell types of action are usually unknown. This thesis identifies the causal variants, genes and cell types behind such associations for two blood traits at opposite ends of the hematopoietic hierarchy: circulating CD34+ cell levels and serum immunoglobulin levels. Signals were fine-mapped, interpreted against sorted-cell expression and chromatin data, and tested by reporter assay, factor knockdown and genome editing.

Blood CD34+ cell levels had not previously been subjected to... (More)
Blood and immune cell traits vary continuously between healthy individuals and are largely heritable, making them tractable to genome-wide association analysis. The variants they implicate are mostly non-coding, and their target genes, mechanisms and cell types of action are usually unknown. This thesis identifies the causal variants, genes and cell types behind such associations for two blood traits at opposite ends of the hematopoietic hierarchy: circulating CD34+ cell levels and serum immunoglobulin levels. Signals were fine-mapped, interpreted against sorted-cell expression and chromatin data, and tested by reporter assay, factor knockdown and genome editing.

Blood CD34+ cell levels had not previously been subjected to genome-wide analysis; in 13,167 individuals, eight loci were implicated. The strongest resolved to an intronic variant that abolishes a binding site for the transcription factor MYB and lowers expression of PPM1H, a phosphatase with no prior role in hematopoiesis. Reducing PPM1H raises stem cell output, making it a candidate mobilization target. A second locus resolved to a variant removing a GATA2 site from a progenitor enhancer.

Nine immunoglobulin traits measured in 114,697 individuals yielded 504 associations, most of them new. Together they describe the B cell system stage by stage, from lineage commitment to antibody clearance, and implicate genes with no described role in immunity. The largest effects fall on a few control points where series of alleles tune antibody output continuously; at the receptor TNFRSF13B (TACI) and its ligand TNFSF13 (APRIL) these run from immunodeficiency-causing variants to one raising plasma cell cancer risk.

Quantitative traits measured in unselected populations therefore act as forward genetic screens of human tissue, recovering the regulators of normal physiology together with genes in which more severe variation causes disease. (Less)
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author
supervisor
opponent
  • Professor Pan-Hammarström, Qiang, Karolinska Institutet, Stockholm
organization
publishing date
type
Thesis
publication status
published
subject
keywords
GWAS, gene regulation, hematopoietic stem cell, immunoglobulins, B cell
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2026:123
pages
90 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
defense date
2026-10-30 13:00:00
ISSN
1652-8220
ISBN
978-91-8021-921-1
language
English
LU publication?
yes
id
62d0dc70-8104-4a53-966d-2fe1fa443c0e
date added to LUP
2026-09-30 11:12:36
date last changed
2026-10-08 13:14:09
@phdthesis{62d0dc70-8104-4a53-966d-2fe1fa443c0e,
  abstract     = {{Blood and immune cell traits vary continuously between healthy individuals and are largely heritable, making them tractable to genome-wide association analysis. The variants they implicate are mostly non-coding, and their target genes, mechanisms and cell types of action are usually unknown. This thesis identifies the causal variants, genes and cell types behind such associations for two blood traits at opposite ends of the hematopoietic hierarchy: circulating CD34+ cell levels and serum immunoglobulin levels. Signals were fine-mapped, interpreted against sorted-cell expression and chromatin data, and tested by reporter assay, factor knockdown and genome editing.<br/><br/>Blood CD34+ cell levels had not previously been subjected to genome-wide analysis; in 13,167 individuals, eight loci were implicated. The strongest resolved to an intronic variant that abolishes a binding site for the transcription factor MYB and lowers expression of PPM1H, a phosphatase with no prior role in hematopoiesis. Reducing PPM1H raises stem cell output, making it a candidate mobilization target. A second locus resolved to a variant removing a GATA2 site from a progenitor enhancer.<br/><br/>Nine immunoglobulin traits measured in 114,697 individuals yielded 504 associations, most of them new. Together they describe the B cell system stage by stage, from lineage commitment to antibody clearance, and implicate genes with no described role in immunity. The largest effects fall on a few control points where series of alleles tune antibody output continuously; at the receptor TNFRSF13B (TACI) and its ligand TNFSF13 (APRIL) these run from immunodeficiency-causing variants to one raising plasma cell cancer risk.<br/><br/>Quantitative traits measured in unselected populations therefore act as forward genetic screens of human tissue, recovering the regulators of normal physiology together with genes in which more severe variation causes disease.}},
  author       = {{Ali, Zain}},
  isbn         = {{978-91-8021-921-1}},
  issn         = {{1652-8220}},
  keywords     = {{GWAS; gene regulation; hematopoietic stem cell; immunoglobulins; B cell}},
  language     = {{eng}},
  number       = {{2026:123}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Natural genetic variation as a discovery platform for human immunology and hematopoiesis}},
  url          = {{https://lup.lub.lu.se/search/files/262037481/Ali_thesis_LUCRIS.pdf}},
  year         = {{2026}},
}