Study of two isolated populations in Greece sheds light on genetic causes of blood disorders

A new study of the hematological (blood cell) traits found in two different populations of isolated villagers in Greece sheds new light on blood disorders, including sickle cell anemia and thalassemia.

The study appears Jan. 21 in the peer-reviewed online journal Nature Scientific Reports.

The number, size and shape of blood cells vary widely among individuals. Hematological traits are linked to cancers and infections, and to cardiovascular, metabolic and immune disorders. 

Mutations in the genes that produce hemoglobin can lead to disorders including sickle cell anemia and alpha and beta thalassemia (another form of anemia). These inherited anemias are seen in parts of Africa, the Mediterranean, the Middle East, India and Southeast Asia, overlapping regions with a history of endemic malaria. 

Whole-genome sequencing 

The new study used data on the blood samples from 1,457 individuals from isolated mountain villages on the Greek island of Crete and 1,617 from long-isolated Pomak villages in northern Greece. 

Pomaks are Bulgarian-speaking Muslims who live as a sometimes-persecuted minority population in northwestern Turkey, Greece and Bulgaria. Their population is thought to number about 300,000. Some Pomaks have inhabited the same villages for more than 500 years, which makes them an ideal population for studying genetic changes over time. 

The study used techniques known as whole-genome sequencing and deep phenotyping to find associations between genes and hemoglobin disorders. Five previously unreported loci on the chromosomes were found to be associated with hematological traits in one or both of the populations. 

The gene variant known as G-allele was found to be associated with an increase in red blood cell count in the Cretan population. This single nucleotide variant was not reported in previous studies of blood traits. 

Four novel loci were found in the Pomak population study, one associated with increased white blood cell count. One of these variants had been observed in a previous study of larger populations.

A novel association with platelet distribution was found on chromosome 9 in the Pomak population which was found in an intron of another gene. 

A region on chromosome 11 displayed the strongest association with red blood cell traits (except the volume percentage of red blood cells known as hematocrit) in the Pomak population. In the Cretan population under study, the same chromosomal region was associated with mean corpuscular hemoglobin concentration (MCHC). 

In both populations the chromosome 11 variations were associated with the three most-frequent mutations in the HBB gene, which codes for Hemoglobin subunit beta protein (also known as beta globin). 

Contrasts with previous studies

The authors note that the moderate to large effects observed in the studies of these two isolated populations contrast with other studies. Another study based on whole-genome sequencing of 3,781 individuals from European cities did not discover any novel associations with blood traits. 

“We hypothesize that the observed enrichment of novel haematological association of rare variants is a consequence of population history,” the authors said. “Genetic drift due to the founder event in these isolated groups may have resulted in increased allele frequencies for the associated variants, which provides better statistical power for discovery of rare variants.”  

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K. Kuchenbaecker et al. Insights into the genetic architecture of haematological traits from deep phenotyping and whole-genome sequencing for two Mediterranean isolated populations, Nature Scientific Reports (21 Jan 2022). 

DOI: https://doi.org/10.1038/s41598-021-04436-9