Art, alpha-1-antitrypsin polymorphisms and intense creative energy: blessing or curse?

Persons heterozygous for Z, S and rare alpha-1-antitrypsin (AAT, SERPIN1A) polymorphisms (ca. 9% of population) are often considered 'silent' carriers with increased vulnerability to environmentally modulated liver and lung disease. They may have significantly more anxiety and bipolar spectrum disorders, nutritional compromise, and white matter disease [Schmechel DE, Browndyke J, Ghio A. Strategies for the dissection of genetic-environmental interactions in neurodegenerative disorders. Neurotoxicology 2006;27:637-57]. Given association of art and mood disorders, we examined occupation and artistic vocation from this same series. One thousand five hundred and thirty-seven consecutive persons aged 16-90 years old received comprehensive work-up including testing for AAT 'phenotype' and level, nutritional factors, and inflammatory, iron and copper indices. Occupations were grouped by Bureau of Labor Standards classification and information gathered on artistic activities. Proportion of reactive airway disease, obstructive pulmonary disease, and pre-existing anxiety disorder or bipolar disorder were significantly increased in persons carrying AAT non-M polymorphisms compared to normal MM genotype (respectively, 10, 20, 21, and 33% compared to 8, 12, 11, and 9%; contingency table, pulmonary: chi2 37, p=0.0001; affective disorder: chi2=171, p=0.0001). In persons with artistic avocation (n=189) or occupation (n=57), AAT non-M polymorphisms are significantly increased (respectively, proportions of 44 and 40% compared to background rate of 9%; contingency table, avocation: chi2=172, p=0.0001; occupation: chi2=57, p=0.0007). Artistic ability and 'anxiety/bipolar spectrum' mood disorders may represent phenotypic attributes that had selective advantage during recent human evolution, an 'intensive creative energy' (ICE) behavioral phenotype. Background proportion of ICE of 7% consists of 49 of 1312 persons with AAT MM genotype (4%), and 58 of 225 persons with non-MM genotypes (26%) (contingency table, chi2=222, p=0.0001). Penetrance of ICE increases in genotypes with lower AAT levels: PiMS, 18%; PiMZ, 44%; PiSS and PiZZ, 100% (five cases). At all ages, persons with non-MM genotype had significantly higher proportion of thiamine deficiency (50% in PiMZ), reactive hypoglycemia (20% in PiMZ), and possibly fatty liver (thiamine: chi2=28, p=0.0001; hypoglycemia: chi2=92, p=0.0001). In older persons, PiMZ genotype had significantly increased proportion (46%) of brain MRI T2 white matter abnormalities (chi2=49, p=0.003). Persons with ICE and MM genotype showed increased prevalence of pulmonary disorders and same signature as S and Z carriers and homozygotes (see above). Z polymorphism was associated with delayed age of onset (average 7 years) for persons with toxic environmental or occupational exposures (log rank, p=0.0001) and more stable cognitive change in persons with neurodegenerative illness (p<0.05). At all ages, ICE phenotype and Z polymorphism were associated with altered copper homeostasis with low or absent non-ceruloplasmin bound copper (p<0.05). AAT polymorphisms which affect iron, lipid and copper metabolism may affect early events in nervous system development, function and response to environmental exposures. AAT may also be a 'switch' for copper metabolism and low 'free' copper would be theorized to provide protection for lipid oxidation and favorably affect beta-amyloid and other aggregation, but possibly alter early 'critical' period of CNS development. AAT polymorphisms may define an important and treatable subset of persons presenting with CNS disorders. This new proposed phenotype for AAT transcends classic pattern of strictly liver and lung disease, and should be considered for proper evaluation and management of patients presenting with classic AAT-related disorders, affective disorders, persons with ICE, white matter disease or multisystem disorders of memory.