A new study analyzes pigment traits and their relationship to diseases

A new study with the GCAT cohort analyzes pigmentary traits and their relationship to diseases

The combined GWAS results for the 13 pigment traits highlight their pleiotropic nature. Three-dimensional Manhattan plot representing on the X axis the chromosomal positions of genome-wide significant associations; on the Y axis, the pigment traits represented by the colors; and on the Z axis, the level of significance of the association, expressed in -log10 (p-value). The colored dots represent the main SNPs associated with one or more pigment traits. Black circles represent SVs, overlapping significant GWAS hits. The red dashed lines represent the mapping of genome-wide significant associated SNPs with several pigmentation traits mapping the SLC45A2, IRF4, TYR, HERC2, and MC1R genes. Credit: Genoa (2023). DOI: 10.3390/genes14010149

Researchers from IGTP’s GCAT’Genomes for Life project have analyzed the genetic bases of 13 pigmentary traits and their association with diseases. The book was published this month in Genoa.

Pigmentary traits, genetically determined, have been widely studied by GWAS, mainly in cohorts of Caucasian ancestry from Northern Europe. However, a lack of information is remarkable in the southern European population. Understand the genetic basis adaptation of skin color in different populations has many implications not only for human evolution, but also for medical practice.

Using the GCAT cohort, Xavier Farré and Natalia Blay, the first two authors of the study, together with Betty Cortés, constructed a comprehensive analysis strategy leading to the identification of diseases associated with the phototype in a total of nearly 20 000 Catalan subjects and exploring 177 ICD-9 diagnoses.

In addition, a genome-wide analysis of over 10 million variants, including structural variants of pigmentary traits, using polygenic risk scores, identified two novel regulatory genes involved in skin color and revealed a shared genetics between diseases and determinants of pigmentation.

“We observed that a light-skinned phototype is strongly associated with non-melanoma skin cancer and other dermatoses and confirmed by the PRS approach the shared genetic basis with certain skin and eye diseases, such as melanoma, non-melanoma skin cancer, basal cell carcinoma. . On another note, darker phototype associated with vitiligo and cataracts. The study also identified a link with obesity and hypertension” , explains Rafael de Cid, lead author of the study.

Genetic analyzes revealed 37 risk loci associated with most pigmentary traits, including 16 genes significantly associated with at least two pigmentary traits. Some of them have been widely reported, such as MC1R, HERC2, OCA2, TYR, TYRP1, SLC45A2, and three new candidates (C1QTNF3, C1QTNF3-AMACR and LINC02876) with regulatory potential have been unveiled: a long non-coding RNA ( LINC02876) and nonsense-mediated decay (NMD) mRNA (C1QTNF3-AMACR), defining a putative complex hotspot locus for the fine regulation of pigment traits.

This study unravels the genetic basis of pigmentary traits in the GCAT cohort, being the largest southern European population analyzed to date, extending previous work conducted primarily in cohorts of northern European Caucasian ancestry, and including a broader disease spectrum than previous studies.

“Our results highlight the importance of integrating population information to tailor personalized care approaches to manage differential risks general population, being of great importance in modern mixed populations. Skin color genetics, as a proxy for skin functionality, could help illness screening in mixed populations,” says de Cid.

Further research involving multi-ancestry cohorts may draw definitive conclusions about the association between pigment characteristics and disease prevalence in different populations.

More information:
Xavier Farré et al, Skin Phototype and Disease: A Comprehensive Genetic Approach to Pigmentary Traits Pleiotropy Using PRS in the GCAT Cohort, Genoa (2023). DOI: 10.3390/genes14010149

Provided by the German Research Institute Trias i Pujol

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