rs4975605 — TERT

TERT's Second Intron — A Variant at the Intersection of Cancer Risk and Brain Resilience

TERT (telomerase reverse transcriptase) is the catalytic engine of telomerase, the molecular complex that rebuilds the protective caps (telomeres) at the ends of chromosomes after each cell division. The 5p15.33 genomic region — where TERT sits — is one of the most pleiotropic loci in the human genome, with multiple independent variants independently linked to diverse cancers, telomere length, and now psychiatric resilience. Rs4975605 is an intronic variant at this locus (chr5:1275413, GRCh38) that sits approximately 10 kilobases 5' of the better-characterized rs2736100 variant and appears to tag a distinct functional signal within the TERT regulatory landscape.

The Mechanism

Rs4975605 falls within intron 2 of TERT on the minus-strand gene, though the alleles are reported in forward (plus-strand) orientation: C (reference, common) and A (alternate, risk). Like other intronic TERT variants, it does not alter the protein sequence but is believed to influence TERT gene regulation through allele-specific effects on transcription factor binding or chromatin accessibility in specific tissues. The variant is in partial linkage disequilibrium¹¹ partial linkage disequilibrium
the degree to which this SNP tracks with neighboring TERT variants such as rs2736100, rs2736122, and rs10069690 varies by cancer type, suggesting it tags at least partly independent regulatory variation with neighboring TERT variants, meaning it captures partly distinct biological variation at this locus.

Notably, the biological associations of rs4975605 do not perfectly mirror those of rs2736100. The two variants appear to influence TERT regulation in a tissue- and context-dependent manner: rs4975605 shows stronger associations with germ cell tumors and ovarian cancers — tissues where telomerase reactivation is a near-universal early event — while rs2736100 has stronger associations with leukocyte telomere length and lung adenocarcinoma. This dissociation is biologically informative: the TERT locus contains multiple independent regulatory elements active in different cell types.

The Evidence

Testicular germ cell tumors (TGCT): The most precisely quantified association is with familial TGCT. Kratz et al. (2011, J Med Genet)²² Kratz et al. (2011, J Med Genet)
Variants in or near KITLG, BAK1, DMRT1, and TERT-CLPTM1L predispose to familial testicular germ cell tumour studied 97 familial TGCT cases, 22 bilateral TGCT cases, and 871 controls, finding rs4975605 carried OR 1.68 (95% CI 1.23–2.29, p = 1.24 × 10⁻³) — a substantially elevated risk, notably described as a "second independent association" at the TERT locus beyond the primary signal at rs2853676/rs4246742. This independent signal suggests rs4975605 tags regulatory variation that compounds, rather than merely duplicates, the primary TERT risk at this locus.

Ovarian cancer: Terry et al. (2012, Cancer Epidemiol Biomarkers Prev)³³ Terry et al. (2012, Cancer Epidemiol Biomarkers Prev)
Telomere length and genetic variation in telomere maintenance genes in relation to ovarian cancer risk analyzed 2,112 ovarian cancer cases and 2,456 controls from two large US cohorts, finding rs4975605 among seven TERT SNPs that were significantly associated with ovarian cancer risk. The overall TERT gene-level association was p = 0.00008. Ovarian cancer, like TGCT, is a cancer type where telomerase reactivation is nearly universal and TERT gene regulation is particularly critical for tumor progression.

Lung cancer chemotherapy response: Zhao et al. (2015, PLoS One)⁴⁴ Zhao et al. (2015, PLoS One)
Association of TERT polymorphisms with clinical outcome of non-small cell lung cancer patients studied 1,004 patients with inoperable advanced NSCLC receiving first-line platinum-based chemotherapy. Heterozygous C/A carriers showed a dramatic reduction in clinical benefit rate compared to C/C homozygotes: 56.4% versus 82.9% (adjusted OR 3.58, p = 1.40 × 10⁻⁴). The effect was most pronounced in never-smoking female patients, a subgroup that has distinct TERT biology. This finding is clinically relevant but requires replication in independent cohorts.

Paranoid schizophrenia — a protective association: Rao et al. (2016, Am J Med Genet B)⁵⁵ Rao et al. (2016, Am J Med Genet B)
Variants in TERT influencing telomere length are associated with paranoid schizophrenia risk conducted a case-control study in 1,072 schizophrenia cases and 1,284 controls from a Chinese Han population. The A allele of rs4975605 was associated with significantly reduced schizophrenia risk (OR 0.73, 95% CI 0.60–0.90, p = 0.0026). Mean lymphocyte telomere length was shorter in schizophrenia patients across the sample — consistent with a model in which TERT variants influencing telomere maintenance modulate neurodevelopmental resilience in ways that affect psychiatric disease liability. Notably, a different TERT variant (rs2075786) in the same study correlated directly with telomere length per genotype, but rs4975605's protective effect was not fully explained by telomere length alone, suggesting it may act through additional mechanisms.

No association with colorectal cancer: Hofer et al. (2012, Mol Carcinog)⁶⁶ Hofer et al. (2012, Mol Carcinog) found no significant association with colorectal cancer or polyp risk among seven TERT SNPs including rs4975605, suggesting the variant's cancer associations are tissue-specific.

Practical Actions

The dual nature of rs4975605 — increased cancer risk in germ cell and ovarian cancers, but protection against schizophrenia — reflects the broader TERT paradox: higher telomerase activity supports proliferating cell survival, which can be beneficial (neuronal maintenance, tissue homeostasis) or harmful (enabling cancer). For A allele carriers, the cancer associations are modest at the individual variant level and most clinically meaningful when considered alongside family history and other TERT locus variants. The chemotherapy response finding has direct implications for NSCLC patients considering platinum-based regimens.

Interactions

rs2736100 (TERT, intron 2, chr5:1,285,974): The best-characterized TERT longevity-cancer variant, with direct effects on leukocyte telomere length and strong associations with lung adenocarcinoma, glioma, and myeloproliferative neoplasms. Rs4975605 and rs2736100 are in partial but incomplete LD — combined risk alleles at both loci may represent additive burden on TERT regulatory function in susceptible tissues.

rs2853676 (TERT): Another independent TERT signal for testicular and other cancers. Kratz et al. identified the primary testicular cancer TERT signal at rs2853676/rs4246742, with rs4975605 as an additional independent signal, suggesting these variants capture different aspects of TERT regulation in the germline.

rs10069690 (TERT): An intronic variant associated with ovarian cancer, triple-negative breast cancer, and telomere-related cancers. In the Terry et al. ovarian cancer study, rs10069690 and rs4975605 were both among the TERT SNPs significantly associated with risk, suggesting possible interaction or pathway-level burden.