Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals [...], 2021, Levey et al

The D2 dopamine receptor (DRD2) was another top finding from the TWAS analysis (Figure 3 top), with significant predicted decreased expression in the nucleus accumbens. The mesolimbic dopamine reward circuit, of which nucleus accumbens is a critical part, has long been implicated in depression.
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That this gene and brain tissue emerged from hypothesis-free GWAS and TWAS tissue enrichment is a remarkable finding with respect to known biology, and points to the potential value of other novel findings from this kind of research.
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I agree with that last sentence that this seems to be a remarkable finding and supports the potential of GWAS and TWAS, because a decrease in dopamine receptors in the nucleus accumbens seems to be exactly what you would expect to be implicated in depression.

DRD2 in nucleus accumbens was almost the most significant, but NEGR1 in the hypothalamus took the top spot. Top genes in each of the tissues they did TWAS on (reformatted):
Gene-based association analysis was performed by integrating GWAS association statistics and eQTL data of all brain and whole-blood tissues from GTEx v8. To prioritize target genes further, joint effects of gene expression correlation across tissues was leveraged using S-MultiXcan. 153 genes and their best representative tissues were below the Bonferroni corrected significance threshold (1.79×10−7) for predicted gene expression in 14 tissues (Figure 3 top; Supplementary file 2).
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Top genes for each tissue tested were:
  • Amygdala (ZKSCAN4, p=1.65×10−12),
  • anterior cingulate cortex (L3MBTL2, p=1.09×10−14),
  • caudate (ZNF184, p=1.85×10−9),
  • cerebellar hemisphere (PGBD1, p=1.67×10−13),
  • cerebellum (ZSCAN9, p=8.4×10−17),
  • cortex (TMEM161B, p=1.84×10−12),
  • frontal cortex (FAM120A, p=3.25×10−10),
  • hippocampus (ZSCAN12, p=1.14×10−18),
  • hypothalamus (NEGR1, p=3.19×10−25),
  • nucleus accumbens (DRD2, p=1.87×10−20),
  • putamen (LIN28B-AS1, p=2.13×10−12),
  • spinal cord c-1 (HIST1H1B, p=2.90×10−18),
  • substantia nigra (RP11–318C24.2, p=2.41×10−12), and
  • whole blood (ZNF165, p=4.01×10−11).
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