An Exploration of the Genetic Architecture of Pregnancy-Related Linea Nigra and Its Relationship With Pigmentation Phenotypes

Human eye, skin and hair color pigmentation are highly heritable traits influenced by hundreds of genetic loci. The heritability and genetic etiology of the hyperpigmentation trait pregnancy-related linea nigra (PLN), where a dark but usually temporary vertical line develops on the abdomen, is unknown, and our understanding of its relationships with other pigmentation traits is limited. We conducted a genetic study of self-reported PLN in women of European ancestry, using a genome-based restricted maximum likelihood (GREML) method to estimate PLN heritability, performing a genomewide association study (GWAS) to explore the genetic factors underlying PLN, and calculating polygenic risk scores (PRS) to assess whether this trait shares genetic liability with two other skin pigmentation phenotypes, skin colour and mole count. We found 35% of the variance in developing PLN was explained by common genetic variation. The GWAS revealed four genomic loci suggestively associated (<i>p</i> values ≤ 1 × 10^-6) with PLN: rs1263154 near the <i>UPP2</i> gene (<i>p</i> = 9.0 × 10^-7), rs26331 near <i>SEMA6A</i> (<i>p</i> = 6.6 × 10^-7), rs78371540 in <i>OLFM3</i> (<i>p</i> = 5.5 × 10^-7), and rs72693263 near <i>FLRT2</i> (<i>p</i> = 1.1 × 10^-7). Of these genes only <i>OLFM3</i> has been previously associated with pigmentation. Our PRS results provide the first evidence that genetic factors underlying skin color and mole count also contribute to the development of PLN in women of European ancestry.