Psychiatric GWAS Cross-Reference Report

Visual Risk Profile

ADHD 2022 37.5% risk

GAD Symptoms 2026 30.5% risk

P-Factor 2025 45.2% risk

Major Depression 2025 57.7% risk

Bipolar Disorder 2024 60.5% risk

Schizophrenia 2022 67.3% risk

Anxiety Disorder 2026 69.7% risk

The chr6 HLA/MHC region (25-33 Mb) is the single most impactful region in your genome for psychiatric genetics. You carry homozygous risk alleles across this entire region, consistent across schizophrenia (76% risk), anxiety (85%), MDD (72%), and bipolar (68%).

What's happening biologically

• C4A Complement (Sekar et al., 2016): Higher C4A expression drives overactive synaptic pruning — microglia eliminate too many synapses, especially in the prefrontal cortex during adolescence. This is the established mechanism for the MHC-schizophrenia link.
• Classical HLA alleles: Pro-inflammatory HLA haplotypes increase TNF-alpha and IL-6 production, crossing the blood-brain barrier and disrupting serotonergic and GABAergic circuits — directly relevant to anxiety and mood.
• Autoimmune overlap: The same variants confer risk for Type 1 diabetes, celiac disease, lupus, multiple sclerosis. There is established epidemiological co-occurrence between autoimmune and psychiatric conditions.
• Developmental timing: Complement-mediated pruning peaks during adolescence (ages 16-25), precisely when schizophrenia onset typically occurs.

Your top HLA risk variants

Your 30 largest-effect risk alleles are all in the chr6 HLA region for schizophrenia, with effect sizes of 1.18-1.35x per allele (the largest in any GWAS). Being homozygous doubles the contribution.

The DRD2 locus (chr11:113.2-113.5M) is your second-strongest signal, hitting genome-wide significance across MDD, schizophrenia, P-factor, and near-significant for anxiety and bipolar.

Key variants you carry (homozygous risk)

Biological impact

• These are regulatory variants reducing DRD2 expression in the striatum
• Lower D2 receptor availability leads to blunted reward prediction signaling, anhedonia, and motivational deficits
• DRD2 is the primary target of all antipsychotic medications
• Lower baseline D2 = reward deficiency = increased addiction vulnerability
• Partial agonists (aripiprazole) may be better tolerated than full D2 blockers in this genotype

ADHD is genetically distinct from your mood/psychosis profile. You carry fewer risk alleles (37.5%) and the risk alleles you do have are in different genes on different chromosomes.

Your ADHD homozygous risk loci

The 17q21.31 region (CRHR1/MAPT) is your most consistently protective region. All 20 SNPs tested in this region show protective alleles for GAD anxiety.

17q21.31 inversion status

Tag SNP rs8070723 = AA → You are H1/H1 (homozygous non-inverted haplotype, most common in Europeans). Within this H1 background, you carry the favorable variants at CRHR1.

Why this matters

• CRHR1 is the receptor for corticotropin-releasing hormone — the master switch of the fight-or-flight stress response
• Protective variants here are associated with blunted cortisol response to stress and reduced anxiety/depression risk, particularly after childhood adversity (gene-environment interaction)
• MAPT (tau): H1 haplotype carries slightly elevated risk for tauopathies (late-life, small effect)
• CRHR1 antagonists have been trialed for anxiety and depression — this locus is pharmacologically actionable

You carry heterozygous risk at multiple CACNA1C variants (rs1006737, rs2159100, rs4765905, etc.) — genome-wide significant for bipolar disorder.

Biology

• CACNA1C encodes the Cav1.2 L-type calcium channel, critical for synaptic plasticity, CREB signaling, and long-term potentiation
• Risk alleles increase CACNA1C expression → elevated calcium influx → destabilized neuronal excitability
• This may shift circuits between hyperexcitable (mania) and compensatory hypoactive (depression) states
• Lithium, the gold-standard bipolar treatment, attenuates calcium signaling
• Dihydropyridines (nimodipine, isradipine) block this channel and show some antimanic/antidepressant effects in trials
• Timothy syndrome (rare gain-of-function CACNA1C mutations) causes cardiac arrhythmias + autism — proof-of-concept that this pathway matters

You carry heterozygous risk across the FADS gene cluster (chr11:61.5M) for bipolar (***), MDD (***), and P-factor (***).

What these genes do

• FADS1/FADS2 encode fatty acid desaturases — enzymes that convert dietary omega-3 and omega-6 into long-chain polyunsaturated fatty acids (LC-PUFAs)
• LC-PUFAs are critical for brain membrane composition and determine the ratio of pro- to anti-inflammatory lipid mediators
• Risk variants alter this enzyme activity, shifting the balance toward more inflammatory lipid profiles

Key findings across serotonin genes

61 SNPs show zero risk alleles at genome-wide significance across 2+ disorders. These are consistently working in your favor.

Multi-disorder protective SNPs

Effect size pattern

At both ADHD and GAD loci, your protective alleles have larger effect sizes than your risk alleles. Your protective alleles punch harder.

Pairwise GW-significant SNP overlap

ADHD is the genetic outlier — almost no shared GW-significant SNPs with other conditions. Anxiety, MDD, bipolar, and schizophrenia share heavily (94-100% directional concordance), primarily through the HLA region.

Risk allele percentage at GW-significant loci, by chromosome. Colors: 70%+ risk, 55-70% mild risk, below 30% protective.

The Three Pillars of Your Genetic Risk Profile

Pillar 1: Immune/Inflammatory (Strongest)

Two independent genomic regions — HLA/C4A (chr6) and FADS1/FADS2 (chr11) — both converge on neuroinflammation. The HLA signal is your single largest genetic loading, driving risk across schizophrenia, anxiety, depression, and bipolar simultaneously. This connects to the growing field of immunopsychiatry and suggests inflammatory pathways as a major axis of vulnerability.

The autoimmune-psychiatric spectrum hypothesis proposes these aren't independent conditions but share upstream immune dysregulation. Mendelian randomization studies confirm causal roles for IL-6 signaling in depression and schizophrenia.

Pillar 2: Dopaminergic Hypofunction

The DRD2/HTR3A super-locus (chr11:113M) reduces D2 receptor expression in the striatum. Combined with your COMT Val/Met genotype and DRD2 Taq1A carrier status, the overall picture is reduced dopaminergic tone in reward circuits. This is transdiagnostic — spanning depression (anhedonia), bipolar, schizophrenia, and general psychopathology (P-factor).

Pillar 3: Neurodevelopmental Wiring

Your ADHD-specific risk loci (FOXP2, CDH8, PTPRF, PCLO) affect how synapses form and how neural circuits are wired during development. These are distinct from the mood/psychosis signals — ADHD shares almost no genetic architecture with other conditions in your profile.

Counterbalancing Protection

• CRHR1 stress axis — consistently protective, suggesting well-regulated HPA axis stress response
• HTR2A / TPH2 serotonin — protective at the 5-HT2A receptor and brain serotonin synthesis
• Effect size asymmetry — your protective alleles have larger individual effects than your risk alleles
• NEGR1 (chr1) — neuronal growth regulator, protective across anxiety, MDD, and SCZ

Pharmacogenomic Highlights

• OPRM1 GG (Asp40 homozygous, rare ~2-5%): Altered opioid signaling, increased pain sensitivity, better naltrexone response. CPIC pharmacogene.
• DRD2 low-expression: Partial D2 agonists (aripiprazole) may be preferred over full antagonists.
• CACNA1C gain-of-function: Lithium targets this pathway; L-type calcium channel blockers are being studied.
• Immune loading: Anti-inflammatory adjuncts (celecoxib, minocycline) show benefit in trials for individuals with immune-related genetic risk.

GWAS Summary Statistics

1. ADHD 2022 — Demontis D, Walters RK, Rajagopal VM, et al. "Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains." Nature Genetics 55, 198-208 (2023). PMID: 36702997
2. GAD Symptoms 2026 — Skelton M, Mitchell BL, et al. "Genome-wide meta-analysis of quantitatively measured generalized anxiety symptoms in individuals of European ancestry." Nature Human Behaviour (2026). N=693,869.
3. Anxiety Disorder 2026 — PGC Anxiety Disorders Working Group. Full anxiety case-control meta-analysis. 122,083 cases / 729,602 controls, European ancestry.
4. Panic Disorder 2019 — Forstner AJ, Awasthi S, et al. "Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression." Molecular Psychiatry 26, 4179-4190 (2021). PMID: 31712720
5. MDD 2025 — Adams MJ, et al. "Genome-wide association study of major depression in 688,808 cases identifies 697 associations at 635 loci." Cell (2025). 412,305 cases / 1,588,397 controls (European, excl. 23andMe). Figshare: 10.6084/m9.figshare.27061255
6. Bipolar Disorder 2024 — O'Connell KS, et al. "Genome-wide association study of bipolar disorder." Nature (2024). PMID: 39843750. 59,287 cases / 781,022 controls. Figshare: 10.6084/m9.figshare.27216117
7. Schizophrenia 2022 — Trubetskoy V, Pardinas AF, Qi T, et al. "Mapping genomic loci implicates genes and synaptic biology in schizophrenia." Nature 604, 502-508 (2022). 76,755 cases / 243,649 controls. Figshare: 10.6084/m9.figshare.19426775
8. P-Factor 2025 — PGC Cross-Disorder Group. "General psychopathology factor (P-factor) GWAS." Cross-disorder shared genetic liability. Figshare: 10.6084/m9.figshare.30359017

Key Biological Studies

9. C4A / Schizophrenia — Sekar A, Bialas AR, de Rivera H, et al. "Schizophrenia risk from complex variation of complement component 4." Nature 530, 177-183 (2016). PMID: 26814963
10. FOXP2 — Vernes SC, Spiteri E, Nicod J, et al. "High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2." Genome Research 17, 1835-1843 (2007). PMID: 17989254
11. CRHR1 / Stress — Binder EB, et al. "Association of CRHR1 haplotypes and HPA axis dysfunction in major depression." Molecular Psychiatry 13, 993-1000 (2008). PMID: 18504432
12. 17q21.31 Inversion — Stefansson H, et al. "A common inversion under selection in Europeans." Nature Genetics 37, 129-137 (2005). PMID: 15654335
13. CACNA1C / Bipolar — Yoshimizu T, Pan JQ, Bhatt DK, et al. "Functional implications of a psychiatric risk variant within CACNA1C." Molecular Psychiatry 20, 162-169 (2015). PMID: 25403839
14. DRD2 Regulatory Variants — Schizophrenia Working Group of the Psychiatric Genomics Consortium. "Biological insights from 108 schizophrenia-associated genetic loci." Nature 511, 421-427 (2014). PMID: 25056061
15. OPRM1 Pharmacogenomics — Kranzler HR, Gelernter J, et al. "Variation in OPRM1 moderates the effect of desire to drink on subsequent drinking and its attenuation by naltrexone treatment." Addiction Biology 18, 193-201 (2013). PMID: 22340009
16. Autoimmune-Psychiatric Overlap — Benros ME, et al. "Autoimmune diseases and severe infections as risk factors for schizophrenia." American Journal of Psychiatry 168, 1303-1310 (2011). PMID: 22193673
17. IL-6 and Depression (MR) — Khandaker GM, et al. "Shared mechanisms between coronary heart disease and depression." Molecular Psychiatry 25, 1477-1486 (2020). PMID: 30886334
18. FADS / Brain Lipids — Ameur A, et al. "Genetic adaptation of fatty-acid metabolism: a human-specific haplotype increasing the biosynthesis of long-chain omega-3 and omega-6 fatty acids." American Journal of Human Genetics 90, 809-820 (2012). PMID: 22503634
19. Anti-inflammatory Adjuncts — Zheng W, et al. "Adjunctive celecoxib for schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials." Journal of Psychiatric Research 92, 139-146 (2017). PMID: 28412599

Data Sources & Tools

• Genotype data: 23andMe v5 chip, build GRCh37/hg19 (downloaded August 2022)
• PGC downloads: pgc.unc.edu/for-researchers/download-results/
• Figshare collections: PGC Figshare Collection
• Analysis: Custom Python scripts performing SNP matching by rsID, allele-aligned effect direction comparison, and unweighted risk allele counting. No LD clumping or population-matched PRS methodology was applied.

Analysis scripts: adhd_gwas_crossref.py, anxiety_panic_gwas_crossref.py, multi_disorder_gwas.py, cross_disorder_exploration.py, detailed_locus_exploration.py, deep_exploration_2.py, final_investigation.py