The genetic architecture of human brainstem structures and their involvement in common brain disorders

Abstract

Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.

Fig. 1. Analysis of GWAS discovery sample identifies 61 loci associated with brainstem volumes.

a GCTA-based heritability estimates for the brainstem volumes in the discovery sample of n = 27,034 participants from the UK Biobank. All brainstem volumes showed substantial heritability, with higher estimates for the whole brainstem (h₂ = 0.48), midbrain (h₂ = 0.47), and pons (h₂ = 0.47) and lower for the medulla oblongata (h₂ = 0.35) and SCP (h₂ = 0.27). Error bars, s.e. b Q−Q plots for the brainstem volumes of the discovery sample. c Circular Manhattan plots of GWAS for brainstem volumes of the discovery sample. The outermost plot in blue reflects the GWAS of whole brainstem volume, whereas, from the periphery to center, the turquoise, green, gray/blue, and cyan plots indicate the GWAS of the midbrain, pons, SCP, and medulla oblongata volumes, respectively. Red circular lines indicate genome-wide significance and the red radial lines are significant loci (two-sided P < 5e−8). d Venn diagram showing number of genes mapped by the four different strategies in the discovery sample, i.e., positional gene (blue), expression quantitative trait loci (eQTL; yellow), and chromatin interaction mapping (red), and identification by the GWGAS (green). Seventeen genes were identified by all four approaches. Whole whole brainstem. SCP superior cerebellar peduncle. Medulla medulla oblongata. GW(G)AS genome-wide (gene-based) association analyses. GCTA genome-wide complex trait analysis.

Fig. 2. Manhattan plots from the genome-wide gene-based association analyses for volumes of the whole brainstem.

a midbrain b pons c superior cerebellar peduncle d, and medulla oblongata e in the discovery sample. Thirty-six genes were associated with whole brainstem volume and 22, 37, 10, and 17 genes were associated with volumes of the midbrain, pons, superior cerebellar peduncle, and the medulla oblongata, respectively. Twenty-two of the genes were only associated with whole brainstem volume, whereas 13, 14, 6, 5 genes were only significant for volumes of the midbrain, pons, superior cerebellar peduncle, and the medulla oblongata. The red horizontal lines indicate genome-wide significance threshold of two-sided P < 2.7e−6, i.e., 0.05/18,447 genes.

Fig. 3. Genetic overlap between brainstem volumes and common brain disorders.

a Conditional Q–Q plots for whole brainstem volume conditioned on SCZ (left) and vice versa (right), demonstrating genetic overlap. b Conditional Q–Q plots for whole brainstem volume conditioned on PD (left) and vice versa (right), showing genetic overlap between these phenotypes. c Conditional Q–Q plots for whole brainstem volume conditioned on BD (left) and vice versa (right), demonstrating genetic overlap. d Enhanced discovery of genetic loci for each of the brainstem volumes when conditional false discovery rate analyses were run for each of the brainstem volumes conditioned on the eight brain disorders. These analyses revealed a total of 208 genetic loci for whole brainstem volume, and 111, 270, 55, and 125 loci for volumes of the midbrain, pons, SCP, and medulla oblongata, respectively. These genetic regions were located in 52 unique genetic loci for whole brainstem volume, and 29, 63, 21, and 25 unique loci for volumes of the midbrain, pons, SCP, and medulla oblongata. e conjunctional false discovery rate analysis detected shared genetic loci across brainstem volumes and the eight clinical conditions. The largest numbers of shared loci were found for SCZ (31), BD (14), and PD (17), whereas 8, 4, 6, 9, and 5 genetic loci were jointly shared for ASD, ADHD, MD, AD, and MS, respectively, and the brainstem volumes, when applying a conjunctional FDR threshold of 0.05. WBS whole brainstem. MID midbrain. SCP superior cerebellar peduncle. MED medulla oblongata. ADHD attention-deficit/hyperactivity disorder. ASD autism spectrum disorders. BD bipolar disorder. MD major depression. SCZ schizophrenia. AD Alzheimer’s disease. MS multiple sclerosis. PD Parkinson’s disease.

Fig. 4. Manhattan plots for genetic loci shared between brainstem volumes and eight common brain disorders.

a 4 shared loci in ADHD, b 9 shared loci in ASD, c 14 shared loci in BD, d 6 shared loci in MD, e 31 shared loci in SCZ, f 5 shared loci in AD, g 5 shared loci in MS, and h 17 shared loci in PD. WBS whole brainstem. MID midbrain. SCP superior cerebellar peduncle. MED medulla oblongata. ADHD attention-deficit/hyperactivity disorder. ASD autism spectrum disorders. BD bipolar disorder. MD major depression. SCZ schizophrenia. AD Alzheimer’s disease. MS multiple sclerosis. PD Parkinson’s disease. The black horizontal lines indicate conjunctional false discovery rate threshold of 0.05.

Fig. 5. Volumes of brainstem structures in individuals with common brain disorders compared with healthy controls.

Linear models were run covarying for sex, age, age², intracranial volume, and scanner site. The analyses for volumes of midbrain, pons, SCP, and medulla oblongata were run both with and without covarying for whole brainstem volume. The figure depicts the resulting case-control differences in Cohen’s d, whereas group differences in mm³ are presented in Supplementary Fig. 14. There were differential volumetric alterations in individuals with BD, SCZ, DEM, MCI, MS, and PD as indicated by black frames, after controlling for multiple testing using false discovery rate (Benjamini–Hochberg, accounting for all 99 tests). ADHD attention-deficit/hyperactivity disorder. ASD autism spectrum disorders. BD bipolar disorder. MDD major depressive disorder. PSYMIX non-SCZ psychosis spectrum diagnoses. SCZRISK prodromal SCZ or at risk mental state. SCZ schizophrenia. DEM dementia. MCI mild cognitive impairment. MS multiple sclerosis. PD Parkinson’s disease. WBS whole brainstem. SCP superior cerebellar peduncle. Medulla medulla oblongata.