## 3 Results
### Lysophosphatidylcholine lysoC a C20:3, HDL, LDL, and Total Cholesterol Are Reduced in AF Cases  
From all 175 tested metabolites, only lysophosphatidylcholine lysoC a C20:3 showed a significant difference in concentrations between AF cases and controls (41% lower concentration in AF cases compared to controls; effect size: \(-\)1.075; adjusted \(p\)-value: 0.005) (Figure 4).  
To investigate the potential relationship between lysoC a C20:3 and medication, we first identified all ATC level 2 medication taken by at least 10 AF cases and subsequently tested for an influence of this medication on the metabolite's concentration. No significant difference in concentration between treated and untreated controls was observed for any of the tested medications, suggesting that this metabolite is most likely independent of these treatments. We also found that in the family described above, lysoC a C20: 3 is significantly lower in the nine available relatives (whether or not they have AF) (individuals III-2, III-3, III-4, IV-1, IV-3, IV-4, IV-5, IV-6, and IV-7, Figure 3) compared to the other CHRIS participants (24% lower concentration, \(p\)-adj = 0.031) (Figure 5). Interestingly, among family members, the two AF cases with a reported medically diagnosed AF (III-3 and IV-3, Figure 3) had the lowest values for lysoC a C20: 3.  
Figure 3: Minimal pedigree containing investigated AF cases. For clarity, the pedigree starts with the second generation and displays only the successors of persons with AF; a full pedigree spanning up to 5 generations is provided in Figure S2. Gray symbols indicate known, non-participating, and therefore not phenotyped individuals without further information. The three AF cases are highlighted by black symbols, whereas white symbols refer to unaffected study participants. Age groups (in decades) are provided in the second line below each individual: 20s, age 18 to 29 years; 30s, age 30 to 39 years; etc.; 70+, 70 years or older. The third line presents information on the 10 s ECG P wave, which is either zero (P = 0) or not zero (P > 0). The last line provides detailed genotype information for the loci of interest. Homozygous carriers of the reference allele of variant rs745582874 on chromosome 1 are shown as “aa”, and heterozygous carriers of this variant are marked by “aA”. The same type of information is encoded for rs768476991 on chromosome 13 using the letters “bb” and “BB”, respectively. Genotype information refers to the HRC-imputed data set unless followed by an additional “(S)”, which denotes confirmation by Sanger sequencing. A hyphen (“-”) is displayed for missing genotype information. Persons with a question mark (“?”) inside their symbol have an incomplete phenotype characterized by missing information on drug intake.  
We also tested concentrations of HDL, LDL, and total cholesterol in blood samples of participants not being treated with lipid modifying agents. HDL showed a slight tendency of a lower concentration in AF cases (50.13 mg/dL vs. 53.97 in controls, \(p\)-value = 0.072), while both LDL and total cholesterol levels were significantly lower (LDL: 76.6 md/dL vs. 91.34 in controls, \(p\)-value = 0.0003; total cholesterol: 146.39 mg/dL vs. 162.47, \(p\)-value = 0.0014).