Genome-wide association study of infant fussiness and crying in European and multi-ancestry cohorts

Importance: Infant fussiness impacts infants, their families and their healthcare providers but the underlying causes and mechanisms are not understood.Objective: To identify the common genetic architecture of infant fussiness and its shared genetic pathways with concurrent conditions as well as later outcomes.Design: Genome-wide association study meta-analysis of infant fussiness in the first postnatal year.Setting: Five European-ancestry population-based cohorts based in Norway, England and the Netherlands (total N=78128) and two multi-ancestry (Black African/mixed and East Asian) cohorts (total multi-ancestry meta-analysis including European cohorts N=156599). The association between polygenic scores for fussiness and brain phenotype was studied in an independent cohort, the developing Human Connectome Project (N=264).Main outcome and measures: Parent-reported infant fussiness in the first postnatal yearResults: Infant fussiness showed a significant SNP-based heritability (h2SNP; 8.18%; SE, 0.78%). Infant fussiness shared common genetic architecture (genetic correlation, rg) with toddler emotionality (rg, 0.40; SE, 0.08, P=1x10-6), toddler shyness (rg, 0.25; SE, 0.07, P=2x10-4), adult neuroticism (rg=0.14, SE, 0.04, P=5x10-4), adult BMI (rg, -0.12; SE, 0.03; P=2x10-4), and infantile hypertrophic pyloric stenosis (rg, 0.21; SE, 0.08; P=1x10-2). The polygenic score for infant fussiness was positively associated with both the volume of frontal white matter and volume of the medial temporal lobe in newborn infant brains (FWE P<0.02). The European-ancestry GWAS identified a genome-wide significant variant on chromosome 13, rs1504440 that was mapped via chromatin interaction to SLITRK5, which is expressed in the central nervous system and involved in neuronal development. Multi-ancestry analyses identified three further genome-wide significant loci.Conclusions and relevance: Infant fussiness is common and can be a source of concern for parents and clinicians. Our results, which show that infant fussiness is associated with genomic variation, may help both parents and healthcare providers understand this behaviour. The common genetic variation associated with fussiness is also associated with later toddler temperament, adult personality and some aspects of physical health, and with infant brain structures involved in emotional regulation.