About the study

Copy number variants reveal divergent genetic and diagnostic cortical signatures across psychiatric disorders. Kumar K, Liao Z, Kopal J, … Thompson PM, Jacquemont S. Preprint available; revised version under review at Communications Medicine.

How it was done

We measured the cortex in two ways, thickness and surface area, and compared standardized group differences (Cohen’s d, adjusted for age, sex and scanning site) across three kinds of data that were analysed separately. For 11 copy number variants and sex chromosome aneuploidies we had individual brain MRI scans of carriers and controls; for 7 more variants we used published estimates. For psychiatric diagnoses we used published case-control results from the ENIGMA consortium: 9 main case-control groups, with medication subgroups and age-stratified groups as further analyses. For common variants we looked up disorder-linked variants in a large genetic study of cortical structure and tested polygenic risk scores in UK Biobank.

Regional maps (34 regions, averaged across hemispheres) were summarised into one shared pattern per data type and compared with the sensorimotor-to-association gradient using spin tests. The full methods, statistics and sensitivity analyses are in the paper.

Data sources

Data Sample Source
Rare variants, individual-level MRI 730 carriers of 11 CNVs or sex chromosome aneuploidies and 870 controls (individual-level MRI) This study; cohorts listed in the paper
Rare variants, published estimates 7 further variants from published meta-analyses PMID 36865328, PMID 34509290, PMID 37480975
Psychiatric diagnoses 8 disorders in 9 ENIGMA case-control groups ( 13,812 cases); medication subgroups; age-stratified groups as sensitivity analyses ENIGMA: PMID 32539527, PMID 29960671, PMID 27137745, PMID 28461699, PMID 33950164, PMID 39025633
Common variants, cortical lookup cortical GWAS of 51,665 people (Grasby et al. 2020) Psychiatric Genomics Consortium and ENIGMA genome-wide studies
Polygenic risk scores 31,413 UK Biobank participants of European ancestry who carry none of the studied CNVs UK Biobank

The site shows only results reported in the paper and its supplementary tables. It does not host individual-level data or genome-wide summary statistics.

Limitations

  • The results are group-level associations from cross-sectional data; they do not show cause and effect, and they do not apply to any one person.
  • Common-variant analyses used European-ancestry genetic studies and UK Biobank participants of European ancestry; the results may differ in other ancestries.
  • Medication status may also reflect illness severity or duration, which could not be separated here.
  • The analysis of opposing effects covers bipolar disorder and schizophrenia only; evidence from the variance test is stronger for schizophrenia.
  • The set of rare variants depended on which carriers had MRI scans available.

Glossary

Surface area

The area of the cerebral cortex, the folded outer sheet of the brain. Surface area is largely set during fetal development, when the pool of cortical progenitor cells expands.

Cortical thickness

The depth of the cortical sheet. Thickness keeps changing through adolescence and adulthood and can differ with age, illness and medication.

Copy number variant (CNV)

A rare genetic change in which a segment of a chromosome is missing (deletion) or present in an extra copy (duplication). The CNVs studied here are known to raise the risk of psychiatric and neurodevelopmental conditions. Sex chromosome aneuploidies (for example XXY) and trisomy 21 change the dose of whole chromosomes and are included with them.

Common variant

A single-letter difference in DNA carried by many people. Large genome-wide studies have linked hundreds of such variants to each psychiatric disorder; each one has a very small effect.

Polygenic risk score

A score that adds up a person’s common variants linked to a disorder, weighting each by its effect on disorder risk. It summarises genetic liability but does not diagnose anyone.

Effect size (Cohen’s d)

The difference between a group (carriers or patients) and controls, divided by the spread of the measure. It lets studies of different sizes and scanners be compared on one scale. Here effects are adjusted for age, sex and scanning site.

Shared pattern (first principal component)

For each set of maps (for example, all CNV surface area maps), principal component analysis finds the pattern that best summarises how regions vary together. The map shows each region’s score on that first pattern. Units are arbitrary; only the relative pattern matters.

Sensorimotor-to-association gradient

A well-established ordering of cortical regions, from primary sensory and motor areas (vision, touch, movement), which develop early, to association areas (planning, language, social thinking), which keep developing into adulthood.

Spin test

Neighbouring brain regions tend to have similar values, which can make two maps look alike by chance. The spin test rotates one map many times on the cortical sphere and asks how often a random rotation matches as well as the real map.

Variance ratio

The spread of surface area effects for disorder-linked common variants, divided by the spread for randomly chosen variants with matched allele frequency. Above 1 means the disorder variants have larger effects, in both directions.

Simulated risk-score association (R²)

In simulations, risk scores were built from the measured variant effects, either with their observed mix of directions or with all directions made the same, keeping the sizes unchanged. R² is the share of surface area differences between people that the score explains.

ENIGMA

The ENIGMA consortium combines brain MRI data from many sites worldwide. The diagnosis results shown here use its published case-control summary statistics.

Desikan atlas

A widely used atlas that divides each hemisphere of the cortex into 34 named regions. Values were averaged across the two hemispheres and are drawn on one hemisphere.

How to cite

Kumar K, Liao Z, Kopal J, … Thompson PM, Jacquemont S. Copy number variants reveal divergent genetic and diagnostic cortical signatures across psychiatric disorders. Communications Medicine.

Analysis code for the paper’s figures: GitHub. Contact: . Brain surface: Desikan-Killiany atlas mesh from ggseg3d (Mowinckel and Vidal-Piñeiro, 2020).