Science - USA (2022-04-08)

that reveal the region overlapping rs11080327
to be harboring a cis-regulatory element that
is activated in response to type 1 interferon
( 11 ). Overall, our findings illustrate that varia-
bility in cell activation in vivo could modify
genetic effects on gene expression, which in turn
suggests that genetic differences may not only
predispose individuals to SLE but may also
affect an individual’s response to a disease state.

Discussion

SLE remains a challenging autoimmune disease

to diagnose and treat. The paucity of targeted

therapies, in conjunction with the heteroge-

neity of disease manifestations and treatment

response, highlight the need for improved mo-

lecular characterization. In a large ancestrally

diverse cohort, we demonstrated the use of

mux-seq as a systematic approach to character-

ize changes in cell type composition and cell

type–specific gene expression in adult SLE. We

further showed how integration of population

genetics with single-cell RNA sequencing could

be used to annotate genetic variants with cell

type–specific effects on gene expression associ-

ated with SLE and other autoimmune diseases.

Using mux-seq, we linked compositional

changes to variation in immune cell transcriptional

Perezet al.,Science 376 , eabf1970 (2022) 8 April 2022 9 of 13

Fig. 5. Cell typeÐspecific genetic determi-
nants of gene expression.(A) Cis-genetic
correlation (rG; lower triangular plot), shared
residual correlation (rE; upper triangular plot),
and heritability (h2; diagonal) of eight cell
types and PBMCs. Cis is defined 100 kb within
the transcription start site. (B) Manhattan
plots of shared eQTLs (sh-eQTLs; black) and
cell type–specific cis-eQTLs (cs-eQTLs;
colored) determined by mapping cis-eQTLs
associated with shared and cell type–specific
expression components from decomposition
analysis. Associations are reported as

• log 10 (Pvalue) (yaxis) ordered by chromo-
  somes (xaxis). (C) Enrichment of cs-eQTLs
  (left) and cell type–by–cell type eQTLs
  (CBC-eQTLs; right) for disjoint sets of cell
  type–specific regions of open chromatin.
  P< 0.01, P< 0.001, P< 0.0001
  (Mann-Whitney test). (D) Enrichment of shared
  or cs-eQTLs among GWAS associations for
  seven non–immune-mediated (CAD, coronary
  artery disease; BMI, body mass index;
  T2D, type 2 diabetes; SCZ, schizophrenia; BP,
  bipolar disease; AD, Alzheimer’s disease)
  and nine immune-mediated diseases or traits
  (UC, ulcerative colitis; RA, rheumatoid
  arthritis; PBC, primary biliary cirrhosis;
  MS, multiple sclerosis; IBD, inflammatory
  bowel disease; SLE, systemic lupus
  erythematosus). The Bonferroni corrected
  significance threshold is shown as a
  black line. (EandF) Boxplots of decomposed
  shared and cell type–specific expression
  ofORMDL3(E) andGSDMB(F) in all
  individuals grouped by genotype for
  rs7216389. *COLOC posterior probability

  
  

  0.7. (G) LocusZoom plots of SLE GWAS,
  sh-eQTLs, and cs-eQTLs associated with
  ORMDL3(red) andGSDMB(blue) expression.
  (H) Number of associations identified by a
  modified transcriptome-wide association
  analysis (TWAS) using decomposed shared and
  cell type–specific expression matrices (blue),
  CBC expression matrices (green), or
  pseudobulk PBMCs (red).

  
  

  
  

G

38 38.05 38.1

cM

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Cis-Genetic Correlation (rG)

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***

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Chromosome

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SLE RA Crohn’s

H

RESEARCH | RESEARCH ARTICLE