Utilizing multimodal cortical parcellations to identify novel regions of the human cerebral cortex associated with substance use disorders.

The shared genetic signals between human cerebral cortex and substance use disorders (SUDs) remain largely unknown. Here, we utilized the Human Connectome Project Multi-Modal Parcellation (HCP-MMP) to divide each hemisphere into 180 regions and investigated the genetic overlap between cortical surface area/thickness of these novel regions and four types of SUDs (N > 1 million). We identified 17 and 282 shared genetic loci between global and regional cortical phenotypes and SUDs. The anatomical patterns of genetic overlap were similar for problematic alcohol use and nicotine use, with substantial overlap in the TGd, insula, primary motor cortex, and posterior cingulate cortex. The cortical patterns of SUDs were established along the anatomical and functional hierarchies in the sensorimotor-association (S-A) cortical axis, but were independent of evolutionary hierarchies. Mendelian randomization analyses indicated that genetically predicted reduced surface area of the ventromedial prefrontal cortex (area 25) and frontal opercular area 3 (FOP3), posterior dorsal superior temporal sulcus (STSdp), and posterior insular area 2 (PoI2) were associated with increased risk of cannabis use disorder and opioid use, respectively. Reduced thickness of retrosplenial complex (RSC) was associated with increased risk of problematic alcohol use. However, reduced thickness of fusiform face complex (FFC) was associated with decreased risk of nicotine use. In summary, we provided novel insights into the shared genetic etiology between cortical phenotypes and SUDs under a more refined multimodal cortical parcellation scheme.