Statistical examination of shared loci in neuropsychiatric diseases using genome-wide association study summary statistics
- Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, United Kingdom
- Department of Biostatistics and Health Informatics, King’s College London, United Kingdom
- NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King’s College London, United Kingdom
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom
- Perron Institute for Neurological and Translational Science, Australia
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Australia
- Institute of Health Informatics, University College London, United Kingdom
- NIHR Biomedical Research Centre at University College London Hospitals NHS21 Foundation Trust, United Kingdom
- King’s College Hospital, United Kingdom
Figures
Figure 1
Overview of the analysis procedure for this study.
SuSiE (sum of single effects) is a univariate fine-mapping approach implemented within the R package susieR. ‘coloc’ is an R package for bivariate colocalisation analysis between pairs of traits. h2 …
Figure 2
Genome-wide genetic correlation estimates between all trait pairs.
The heatmap displays genetic correlations (rg) each tile is labelled with the rg estimate and with its standard error in parentheses, alongside the p-value. AD = Alzheimer’s disease, ALS = …
Figure 3 with 1 supplement
Local genetic correlation analyses between trait pairs.
The lower panel displays a heatmap of genetic correlations (rg) across genomic regions where any bivariate analyses were performed; white colouring indicates that the region was not analysed for a …
Figure 3—figure supplement 1
Comparison of positively and negatively correlated genetic loci.
(A) Distribution of genetic correlation estimates (rg) and p-values across trait pairs in local genetic correlation analysis. Trait pairs are denoted by colour and comparisons passing defined …
Figure 4 with 3 supplements
Evidence for colocalisation between amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) in the Chr6:32.63–32.68 Mb region.
(A) Single-nucleotide polymorphism (SNP)-wise p-value distribution between ALS and AD across Chr6:32.63–32.68 Mb, in which colocalisation analysis found 0.90 posterior probability of the …
Figure 4—figure supplement 1
Single-nucleotide polymorphism (SNP)-wise p-value distribution between trait pairs in comparisons where colocalisation analysis suggested a causal variant in both traits.
Colocalisation analysis supported the shared-variant hypothesis for the comparison in (A), and the presence of distinct variants for each trait in (B-G) (see Table 3). Colouring indicates …
Figure 4—figure supplement 2
Heatmaps of linkage disequilibrium (LD) in the 1000 Genomes European reference population across variants assigned to any credible set during univariate fine-mapping of trait pairs (A-G).
LD is shown relative to the single-nucleotide polymorphisms (SNPs) with the highest posterior inclusion probability (PIP) for each credible set, displaying all top PIP SNPs when ties occur. The y-axi…
Figure 4—figure supplement 3
Sensitivity of colocalisation analysis to the prior probability of a shared variant between traits.
The upper panels display analysis at Chr6:32629240–32682213 between amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD). The lower panels are for Chr17:43460501–44865832 between …
Tables
Table 1
Genome-wide association studies (GWAS) sampled.
Each GWAS is a GWAS meta-analysis of disease risk across people of European ancestry.
| Trait | Estimated lifetime risk in population | GWAS | Liability scale h2 (standard error) | ||
|---|---|---|---|---|---|
| Reference | N cases | N controls | |||
| Alzheimer’s disease | 1/10, Chêne et al., 2015† | Kunkle et al., 2019 | 21,982 | 41,944 | 0.093 (0.0155) |
| Amyotrophic lateral sclerosis | 1/350, Alonso et al., 2009; Johnston et al., 2006 | Van Rheenen et al., 2021 | 27,205 | 110,881 | 0.0277 (0.003) |
| Frontotemporal dementia | 1/742, Coyle-Gilchrist et al., 2016 | Ferrari et al., 2014 | 2154 | 4308 | 0.0329 (0.0283) |
| Parkinson’s disease | 1/37, Parkinson’s, 2017 | Nalls et al., 2019 | 15,056 (+18,618 proxies*) | 449,056 | 0.0506 (0.0046) |
| Schizophrenia | 1/250, Saha et al., 2005 | Trubetskoy et al., 2022 | 53,386 | 77,258 | 0.1761 (0.0061) |
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*
Proxy cases from the UK Biobank Cohort.
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†
Estimated from cumulative risk after age 45 after correcting for competing risk of mortality and assuming a lifespan of ~85 years. h2 = heritability.
Table 2
Comparison of genome-wide SNP significance against local genetic correlation significance thresholds in all trait pairs and loci analysed.
All loci analysed showed sufficient local univariate heritability across compared traits to allow bivariate correlation analysis. Subsequent fine-mapping and colocalisation analyses were performed …
| Number of traits in pair with genome-wide significant (p < 5 × 10−8) SNP in locus | Smallest significance threshold for local genetic correlation | |||
|---|---|---|---|---|
| Bonferroni (p < 8.26 × 10−5; 0.05/605) | FDR (pfdr < 0.05) | Nominal (p < 0.05) | Non-significant(p ≥ 0.05) | |
| 0 | 1 | 17 | 77 | 394 |
| 1 | 1 | 4 | 18 | 80 |
| 2 | 0 | 3 | 2 | 8 |
Table 3
Colocalisation analysis conducted across 95% credible sets identified during univariate fine-mapping of trait pairs.
N SNPs refer to the number of SNPs present for both traits and the 1000 Genomes reference panel in the region within colocalisation and fine-mapping analysis.
| Trait | Genomic position (GRCh37) | Local genetic correlation estimate (95% confidence interval) | Fine-mapping credible set for trait | N SNPs | SNP with highest PIP for fine-mapping credible set (nearest gene; sense-strand base pair distance) | Posterior probability for hypothesis¶ | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 1 | 2 | Trait 1 | Trait 2 | H0 | H1 | H2 | H3 | H4 | |||
| AD | PD | Chr6:32576785–32639239† | 0.406 (0.197, 0.648) | 1 | 1 | 958 | rs9271247 (HLA-DQA1; +15,844) | rs3129751 (HLA-DQA1; +13,767) | <0.01 | <0.01 | <0.01 | 0.95 | 0.05 |
| ALS | AD | Chr6:32629240–32682213* | 0.974 (0.717, 1.000) | 1 | 1 | 475 | rs9275477‡ (MTCO3P1; +1260) | rs9275207 (MTCO3P1; +16,191) | <0.01 | <0.01 | <0.01 | 0.10 | 0.90 |
| ALS | FTD | Chr6:32208902–32454577§ | 0.723 (0.370, 1.000) | 1 | 1 | 1709 | rs9268833 (HLA-DRB9; 0) | rs1980493 (BTNL2; 0) | <0.01 | <0.01 | 0.01 | 0.99 | <0.01 |
| 2 | rs9767620 (HLA-DRB9; +1498) | <0.01 | <0.01 | 0.01 | 0.99 | <0.01 | |||||||
| ALS | SZ | Chr6:32208902–32454577§ | - | 1 | 1 | 1711 | rs9268833 (HLA-DRB9; 0) | rs9268219 (C6orf10; 0) | <0.01 | <0.01 | <0.01 | 0.98 | <0.01 |
| Chr12:56987106–58748139 | 0.506 (0.218, 0.807) | 1 | 1 | 2260 | rs113247976 (KIF5A; 0) | rs12814239 (LRP1; 0) | <0.01 | <0.01 | <0.01 | 1.00 | <0.01 | ||
| 2 | rs324017 (NAB2; 0) | <0.01 | <0.01 | <0.01 | 1.00 | <0.01 | |||||||
| PD | SZ | Chr17:43460501–44865832 | 0.595 (0.266, 0.950) | 1 | 1 | 2453 | rs58879558 (MAPT; 0) | rs62062288 (MAPT; 0) | <0.01 | <0.01 | <0.01 | 0.81 | 0.19 |
| SZ | FTD | Chr6:32208902–32454577§ | 0.669 (0.379, 0.990) | 1 | 1 | 1657 | rs9268219 (C6orf10; 0) | rs9268877 (HLA-DRB9; 0) | <0.01 | <0.01 | <0.01 | 1.00 | <0.01 |
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*
Indicates comparisons with genetic correlation analysis p < 8.26 × 10−5 (0.05/605).
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†
Denotes locus extended by ±10 kb for fine-mapping and colocalisation analysis.
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‡
Variant identified in colocalisation as having the highest posterior probability of being shared variant assuming hypothesis 4 is true (see Figure 4).
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§
Differences in fine-mapping solutions across trait pairs in the Chr6:32.21–32.45 Mb locus reflect differences in the SNPs retained after restricting to those in common between the compared genome-wide association studies (GWAS).
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¶
H0 = no causal variant for either trait, H1 = variant causal for trait 1, H2 = variant causal for trait 2, H3 = distinct causal variants for each trait, H4 = a shared causal variant between traits. PIP = posterior inclusion probability, AD = Alzheimer’s disease, ALS = amyotrophic lateral sclerosis, FTD = frontotemporal dementia, PD = Parkinson’s disease, SZ = schizophrenia.
Additional files
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Supplementary file 1
Extended results from local genetic correlation analysis and subsequent fine-mapping and colocalisation analyses across loci correlated between trait pairs.
(a) Results of all bivariate local genetic correlation analyses. (b) Results of colocalisation analyses performed across all single-nucleotide polymorphisms (SNPs) sampled in the region. Number of SNPs refers to the number of SNPs in common between the two traits analysed and present within the 1000 genomes reference panel. Comparisons where univariate fine-mapping identified at least one credible set in each trait were also performed on the basis of these credible sets (see Table 3). Annotations column: * denotes comparisons with genetic correlation analysis p-values below the strict Bonferroni correction threshold; all others passed false discovery rate (FDR) correction. ∆ denotes locus with boundaries extended by ±10 kb compared to the region partition defined in genetic correlation analysis. (c) Overview of credible sets identified across fine-mapping analyses in summary statistics harmonised across trait pairs.
- https://cdn.elifesciences.org/articles/88768/elife-88768-supp1-v1.xlsx
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MDAR checklist
- https://cdn.elifesciences.org/articles/88768/elife-88768-mdarchecklist1-v1.pdf
