Polygenic risk for five psychiatric disorders and cross-disorder and disorder-specific neural connectivity in two independent populations

Abstract

Major psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), autism (AUT), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SZ), are highly heritable and polygenic. Evidence suggests that these five disorders have both shared and distinct genetic risks and neural connectivity abnormalities. To measure aggregate genetic risks, the polygenic risk score (PGRS) was computed. Two independent general populations (N = 360 and N = 323) were separately examined to investigate whether the cross-disorder PGRS and PGRS for a specific disorder were associated with individual variability in functional connectivity. Consistent altered functional connectivity was found with the bilateral insula: for the left supplementary motor area and the left superior temporal gyrus with the cross-disorder PGRS, for the left insula and right middle and superior temporal lobe associated with the PGRS for autism, for the bilateral midbrain, posterior cingulate, cuneus, and precuneus associated with the PGRS for BD, and for the left angular gyrus and the left dorsolateral prefrontal cortex associated with the PGRS for schizophrenia. No significant functional connectivity was found associated with the PGRS for ADHD and MDD. Our findings indicated that genetic effects on the cross-disorder and disorder-specific neural connectivity of common genetic risk loci are detectable in the general population. Our findings also indicated that polygenic risk contributes to the main neurobiological phenotypes of psychiatric disorders and that identifying cross-disorder and specific functional connectivity related to polygenic risks may elucidate the neural pathways for these disorders.

Keywords: Cross-disorder; Disorder-specific; Neural connectivity; Polygenic risk score; fMRI.

Fig. 1

Z-score maps of the meta-analysis for five major psychiatric disorders: (A) ADHD, (B) autism, (C) BD, (D) MDD, (E) schizophrenia. (F) is a binary image of our ROI displaying the overlap between the five maps. MNI coordinates were used.

Fig. 2

Consistent functional connectivity alterations with the bilateral insula associated with the cross-disorder PGRSs (P^T < 0.05) using Dataset 1 and Dataset 2. The values of each voxel in these maps are only 0, − 1 (blue). A value of − 1 indicates significant negative associations separately between functional connectivity in these regions with the defined ROI and PGRS. Only clusters with > 10 voxels are displayed. MNI coordinates are used.

Fig. 3

Consistent disorder-specific functional connectivity alterations associated with the PGRSs(P^T < 0.05) for: (A) autism, (B) BD and (C) schizophrenia, with the bilateral insula using Datasets 1 and 2. The values of each voxel in these maps are only 0, − 1 (blue), and 1 (red). A value of 1 and − 1 indicates significant positive and negative associations separately between functional connectivity in these regions with the defined ROI and PGRS. Only clusters with > 10 voxels are displayed. MNI coordinates are used.

Supplementary Fig. 1

Q-Q plot.

Supplementary Fig. 2

Clusters survived for each regression of each dataset with disorder-specific and cross-disorder PGRS at P^T < 0.05, corrected by AlphaSim algorithm.

Supplementary Fig. 3

Consistent disorder-specific functional connectivity alterations associated with the PGRSs for: (A) autism (P^T < 0.01), (B) autism (P^T < 0.1) and (C) cross-disorder (P^T < 0.1), with the bilateral insula using Datasets 1 and 2, masking by the significant voxels at P^T < 0.05. The t-values are displayed. MNI coordinates are used.